5 Luteolin

Biomedicine & Pharmacotherapy 176 (2024) 116909
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Luteolin as a potential therapeutic candidate for lung cancer: Emerging

preclinical evidence
Jin Zhang a , Yue Ma b, *
a
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, PR China
b
Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004,
PR China
A R T I C L E I N F O A B S T R A C T
Keywords: Lung cancer is a prevalent malignant tumor and a leading cause of cancer-related fatalities globally. However,
Luteolin current treatments all have limitations. Therefore, there is an urgent need to identify a readily available ther
Phytomedicine apeutic agent to counteract lung cancer development and progression. Luteolin is a flavonoid derived from
Lung cancer
vegetables and herbs that possesses preventive and therapeutic effects on various cancers. With the goal of
Pharmacological mechanism
providing new directions for the treatment of lung cancer, we review here the recent findings on luteolin so as to
Treatment
provide new ideas for the development of new anti-lung cancer drugs. The search focused on studies published
between January 1995 and January 2024 that explored the use of luteolin in lung cancer. A comprehensive
literature search was conducted in the SCOPUS, Google Scholar, PubMed, and Web of Science databases using
the keywords "luteolin" and "lung cancer." By collecting previous literature, we found that luteolin has multiple
mechanisms of therapeutic effects, including promotion of apoptosis in lung cancer cells; inhibition of tumor cell
proliferation, invasion and metastasis; and modulation of immune responses. In addition, it can be used as an
adjuvant to radio-chemotherapy and helps to ameliorate cancer complications. This review summarizes the
structure, natural sources, physicochemical properties and pharmacokinetics of luteolin, and focuses on the anti-
lung cancer mechanism of luteolin, so as to provide new ideas for the development of new anti-lung cancer drugs.
1. Introduction and squamous carcinoma [2]. Depending on the stage of the disease at
diagnosis, lung cancer has a 5-year survival rate of 4 %–17 %, indicating
Lung cancer, a common malignant tumor, is one of the leading causes an unfavorable prognosis [3]. Surgery is an effective treatment inter
of cancer-related deaths worldwide. Globally, 1.8 million new cases of vention for most patients in the early stages of the disease; however,
lung cancer are detected yearly, and approximately 1.6 million people only 30 % of NSCLC cases are diagnosed early, and the majority of pa
die from the disease [1]. Lung cancer can be broadly categorized as tients present with symptoms of progression at the time of diagnosis,
either non-small cell lung cancer (NSCLC) or small cell lung cancer which can complicate the implementation of conventional therapies
(SCLC) based on histologic type. SCLC comprises approximately 15 % of (including chemotherapy and radiotherapy) [1]. Recently, patients with
all lung cancers, while NSCLC accounts for the majority of lung cancers, lung cancer, particularly those with NSCLC, now have increased options
which are further classified into adenocarcinoma, large cell carcinoma, for precision cancer treatment owing to the development of
Abbreviations: AIM2, Absent in melanoma 2; AR, Androgen receptors; ARE, Antioxidant response element; Bcl-2, B cell lymphoma-2; CCL2, Chemokine C-C motif
ligand 2; Cdc42, Cell division control protein 42; CDK, Cyclin-dependent kinase; DR, Death receptors; EGFR, Epidermal growth factor receptor; EMT, Epithelial-
mesenchymal transition; ER, Endoplasmic reticulum; FAK, Focal adhesion kinase; HDAC, Histone deacetylase; IFN-γ, Interferon-γ; IKK, IκB kinase; JNK, c-Jun N-
terminal kinase; LC3, Light chain 3; LIMK, LIM structural domain kinase; MOMP, Mitochondrial outer membrane permeabilization; NF-κB, Nuclear factor-kappaB;
NK cells, Natural killer cells; NLRP3, NOD-like receptor family pyrin domain containing 3; Nrf2, Nuclear factor E2 p45-related factor 2; NSCLC, Non-small cell lung
cancer; PCNA, Proliferating cell nuclear antigen; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A; ROS, Reactive oxygen
species; RTKs, Receptor tyrosine kinases; SCLC, Small cell lung cancer; SD rats, Sprague-Dawley rats; SIRT, Sirtuins; Src, Non-receptor tyrosine kinase; TAMs, Tumor-
associated macrophages; TGF-β, Transforming growth factor β; TKIs, Tyrosine kinase inhibitors; TNF, Tumor necrosis factor; TRAILR, Tumor necrosis factor-related
apoptosis-inducing ligand receptor.
* Corresponding author.
E-mail address: mayue_doctor@163.com (Y. Ma).
https://doi.org/10.1016/j.biopha.2024.116909
Received 26 March 2024; Received in revised form 4 June 2024; Accepted 6 June 2024
Available online 8 June 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Zhang and Y. Ma Biomedicine & Pharmacotherapy 176 (2024) 116909
immunotherapies and targeted medicines. Moreover, treatments for luteolin [24]. Most luteolin molecules exist as O-glycosides. Glucose is
lung cancer, including EGFR (epidermal growth factor receptor) in the predominant sugar molecule among the various sugar molecules
hibitors, TKIs (tyrosine kinase inhibitors), and anaplastic lymphoma bonded to luteolin. Other sugar compounds that bond to luteolin include
kinase inhibitors, have benefited considerably from advances in genetics xylose, glucuronic acid, rutinose, arabinose, and rhamnose [27]. The
and molecular biology [4]. Although chemotherapy and novel targeted plant-derived luteolin molecule also exists in aglycone molecules forms,
therapies are promising for the majority of patients with cancer, safety which lack sugar molecules [22]. Interestingly, the aglycone form of
and efficacy issues with currently available treatment options that may luteolin has been proven to have superior anti-inflammatory, antioxi
affect outcomes and patient adherence. Furthermore, multidrug resis dant, and antidiabetic properties when compared to the luteolin-7-O-
tance must be overcome to provide comprehensive cancer care [5]. glucoside form [28].
Botanical extracts are less toxic and have less side effects than synthetic
compounds, and they have garnered significant interest for the treat 3. Biosynthesis of luteolin
ment of a variety of diseases, especially cancer and its complications [6].
In this regard, luteolin is a flavonoid that can be isolated from vegetables Luteolin synthesis starts with phenylalanine [27]. The biosynthesis
and herbs [7] and has preventive and therapeutic effects on a variety of of luteolin via the phenylpropanoid pathway involves the three enzymes
cancers, including breast cancer [8], skin cancer [9], hepatocellular phenylalanine ammonia-lyase (PAL), cinnamic acid 4-hydroxylase
carcinoma [9], and stomach cancer [10]. Luteolin exerts anticancer ef (C4H), and 4-coumaric acid: CoA ligase (4CL) [18]. First, cinnamic
fects by promoting lung cancer cell apoptosis, inhibiting tumor cell acid is generated from phenylalanine in the presence of PAL [18].
proliferation, invasion, and metastasis, aiding chemo-radiotherapy, Following this, cinnamic acid sequentially generates p-coumaric acid
ameliorating cancer complications, and regulating the immune and p-coumaroyl CoA in the presence of C4H and 4CL [21]. Subse
response [11–16]. This article reviews the structure, natural origin, quently, p-coumaroyl CoA sequentially generates naringenin chalcone
physicochemical properties, and pharmacokinetic profile of luteolin, and naringenin in the presence of chalcone synthase (CHS) and chalcone
focusing on its anticancer effects, including detailed mechanisms of isomerase (CHI) [27]. Naringenin exhibits a dual pathway for the gen
action, and emphasizing its therapeutic potential in lung cancer therapy. eration of luteolin: naringenin can generate apigenin via flavone syn
thase (FNS), followed by the generation of luteolin in the presence of
2. Structure, physiochemical properties, and the natural sources flavonoid 3′-hydroxylase (F3′H) [18,21]. Alternatively, naringenin
of luteolin generates eriodictyol via F3′H, followed by the generation of luteolin in
the presence of FNS [27] (Fig. 2).
Among natural plant-derived compounds, the flavonoid luteolin
(3′,4′,5,7-tetrahydroxyflavone) is one of the most highly regarded plant- 4. Methodology
derived chemicals and is abundantly found in various vegetable and
herbaceous plants [17,18]. Along with fruits, plants, and herbs, some This review was performed following the Preferred Reporting Items
popular sources of luteolin are radicchio, Chinese celery, and dried for Systematic Review and Meta-Analysis (PRISMA) checklist. To collect
parsley [19–21]. Luteolin consists of two benzene rings connected by a the relevant academic papers, a comprehensive literature search was
heterocyclic ring to form a C6-C3-C6 carbon skeleton. It is a conducted in the SCOPUS, Google Scholar, PubMed, and Web of Science
yellow-crystalline compound that is soluble in ethanol and diethyl ether. databases using the keywords "luteolin" and "lung cancer." The search
It is also mildly soluble in hot water, resulting in a pale yellow aqueous focused on studies published between January 1995 and January 2024
solution. Its molecular weight is 286.24 g/mol, with a density of that explored the use of luteolin in lung cancer through in vitro and in
1.654 g/cm3, and its chemical formula is C15H10O6 [22,23] (Fig. 1). As vivo bioactivity evaluations and mechanistic studies. Articles were
an important representative flavonoid, luteolin features an oxygen evaluated for inclusion in the study based on the following criteria: (a)
containing heterocyclic ring and two benzene rings. The hydroxyl studies assessing the effects of the luteolin dose, route of administration,
groups at the 5, 7, 3′, and 4′ carbon atoms and 2–3 double bonds are vital and duration of exposure and comparing them to an untreated group
for the pharmacological effects of luteolin (anti-cancer, antioxidant, (control group); (b) studies employing a preclinical experimental model
anti-inflammatory, neuroprotective, etc.) [24,25]. Structure-activity of a pathological condition relevant to lung cancer; (c) the experimental
relationship studies have revealed that the potent antioxidant proper model should be an in vivo or in vitro model, which may include multiple
ties of luteolin are attributed to the hydroxyl groups at the C5, C7, C3′, species; (d) studies assessing apoptotic markers and other relevant
and C4′ sites. Additionally, the carbonyl oxygen at the C4 site is biochemical and molecular parameters; or (e) studies whose results
responsible for the antibacterial properties of the compound. Similarly, involve the inhibition of tumor progression and improvement of prog
bactericidal activity has been attributed to the double bond between C2 nosis. Studies that met any of the following criteria were excluded: (a)
and C3 [22,26]. Plants displaying a variety of substitutions, such as conference abstracts, editorials, or reviews; (b) studies not written in
methylations, hydroxylations, acylations, and glycosylations that pri English; and (c) full text not available. A total of 38 studies were
marily result in O- or C-glycosides, are known to contain flavones like included in this review (Fig. 3). The following information was extracted
and entered into a predefined table: Study types, Species/Cell line,
Models, Interventions, Results, Effects, Neuroprotection mechanism,
and References (Table 1).
5. Mechanisms of luteolin against lung cancer
5.1. Pro-apoptotic effects
Apoptosis is a genetically encoded programmed cell death [29].

Apoptosis is widespread in humans and plays a key role in normal
development and body homeostasis [30]. The molecular mechanism
underlying apoptosis induced by DNA damage resulting from external
stimuli primarily consists of three pathways, namely the mitochondrial,
endoplasmic reticulum (ER), and death receptor pathways, which are all
Fig. 1. The structure of luteolin. closely linked and interact with one another [31,32]. Tumor necrosis
2
Fig. 2. The synthesis of luteolin. The synthesis of luteolin begins with phenylalanine, which, in the presence of PAL, produces cinnamic acid. Cinnamic acid is
subsequently catalyzed by a series of enzymes to produce naringenin, which in the presence of FNS and F3′H ultimately produces luteolin. 4CL, 4-Coumaric acid: CoA
ligase; C4H, Cinnamic acid 4-hydroxylase; CHI, Chalcone isomerase; CHS, Chalcone synthase; F3′H, Flavonoid 3′-hydroxylase; FNS, Flavone synthase; PAL,
Phenylalanine ammonia-lyase.
factor-related apoptosis-inducing ligand receptor (TRAILR) and FAS are dependent apoptosis by disrupting mitochondrial ΔΨm, activating cas
members of the tumor necrosis factor (TNF) family, and both can induce pases, and down-regulating anti-apoptotic members of the Bcl-2 family.
apoptosis in tumor cells [33]. TRAIL binds to the TRAIL receptor After luteolin treatment, the protein expression level of Bax was
(TRAIL-RS) and initiates the apoptotic pathway [34]. The binding of significantly increased, while that of Bcl-2 and Bcl-xl decreased. Luteolin
TRAIL to these death receptors leads to the formation of receptor trimers activated caspase-9, caspase-3, and PARP in a dose-dependent manner
and death-inducing signaling complexes (DISCs), which are pivotal in [42]. Furthermore, luteolin (50 μM) was involved in ER stress-induced
triggering the subsequent activation of caspase-8, a process referred to apoptosis by increasing the markers of ER stress, ORP150, caspase-4,
as exogenous apoptosis [35,36]. The alternate major apoptotic pathway and PDI [43]. Luteolin also sensitized TRAIL-induced apoptosis in can
is the endogenous (mitochondrial) apoptotic pathway, which leads to cer cells. When TRAIL and luteolin were co-administered into cells,
cysteine asparaginase activation and cell death. Mitochondrial outer caspase-8, − 9, and − 3 activation as well as cleavage of the caspase-3
membrane permeabilization (MOMP) is a key process in both the acti substrate PARP were increased. Tumor growth inhibition was also
vation of apoptotic proteases as well as the mitochondrial apoptotic enhanced, tumor weight decreased, and the number of apoptotic cells
pathway [35]. During apoptosis, the key features of MOMP are cysteine increased. Additionally, no significant weight loss or significant adverse
asparaginase activation and the release of cytochrome C, which are effects were observed in the co-treated mice [44]. Mechanistic studies
primarily regulated by the B cell lymphoma-2 (Bcl-2) protein family. suggest that luteolin significantly upregulates p-JNK (c-Jun N-terminal
Additionally, the pro-apoptotic members of this family include Bax and kinase) expression and that JNK activation is involved in the enhance
Bak, which are major effector proteins that activate MOMP on the ment of DR5 expression and regulation of p-Drp1 (Ser616) expression
mitochondrial outer membrane [37–39]. Typically, apoptosis is trig and mitochondrial cytochrome c release [45]. These studies indicate
gered by genetic mutations caused by cell cycle disorders and tumor that luteolin likely participates in the death receptor and mitochondrial
development [40]. Therefore, an important characteristic of cancer is pathways, which regulate apoptosis by modulating the activation of
the ability of cancer cells to escape apoptosis [41]. Further under JNK. Conversely, Ju et al. found that luteolin-induced reactive oxygen
standing of the mechanisms underlying apoptosis in cancer cells is species (ROS) accumulation was critical for enhancing TNF-induced
essential for improved rational treatment with anticancer drugs. nuclear factor-kappa B (NF-κB) inhibition and JNK activation. Luteolin
Luteolin was found to modulate three pathways that mediate completely inhibited the TNF-induced expression of anti-apoptotic
apoptosis. First, luteolin was involved in triggering mitochondria- genes XIAP and MnSOD downstream of NF-κB by inducing ROS, and
3
aging and longevity, diabetes mellitus, and inflammation, with sirt1

being the most highly characterized [56]. Ma et al. found that sirt1 was
involved in decreasing caspase-3 activity and increasing the expression
level of Bcl-2/Bax in NCI-H460 cells. Luteolin also decreased the
expression of sirt1 in a concentration-dependent manner in the
NCI-H460 cell line, increased the Bax/Bcl-2 ratio, and promoted
apoptosis [57]. Zheng et al. also found that luteolin may exert a
pro-apoptotic effect by decreasing the expression of circ_0000190 and
up-regulating the expression of miR-130a-3p, as evidenced by the in
crease in Bax and cleaved caspase-3 levels and the decrease in Bcl-2
levels in H460 and A549 cells [58].
In summary, these studies indicate that luteolin exhibits a strong pro-
apoptotic effect and is directly involved in the regulation of the three
major pathways of apoptosis, which involve regulating JNK activation
as well as oxidation and antioxidant levels. Simultaneously, luteolin can
promote apoptosis by targeting MDM4 and PI3K/AKT/MDM2 to regu
late p53 expression; other substances, including HDAC and sirt1, are
also involved in the modulation of apoptosis by luteolin in lung cancer
cells (Fig. 4).
5.2. Inhibition of cell proliferation
The distinguishing biological characteristic of tumor cells is that they

can supply themselves with sufficient growth signals and exhibit un
limited proliferation ability. Malignant proliferation is one of the
fundamental reasons why it is difficult to completely eliminate tumor
Fig. 3. Literature inclusion and exclusion flow diagram. cells [59,60]. Altering cell cycle distribution and inducing cell cycle
inhibition are considered effective anti-cancer approaches [61,62]. The
the activation of JNK was significantly increased and persisted for over mitotic cycle in tumor cells can be split into four phases: mitosis (M
2 h [46,47]. Mechanistic studies have revealed that ROS-induced JNK phase), late DNA synthesis (G2 phase), pre-DNA synthesis (G1 phase),
activation is dependent on the degradation of MKP-1, the major phos and DNA synthesis (S phase) [63,64]. Cell cycle progression depends on
phatase responsible for JNK inactivation. Furthermore, luteolin stimu the precise and tight regulation of various regulator levels, the core of
lates JNK activation through ROS-mediated degradation of MKP-1 [48]. which is the cyclin-CDK complex, formed by the binding of cyclin and
Notably, luteolin is also believed to possess both pro-oxidant and cyclin-dependent kinase (CDK) [65]. The key cyclin-CDK complexes
anti-oxidant effects owing to its molecular structure [49]. Leung et al. involved in cell cycle regulation include cyclin D-CDK4/6, cyclin
found that Mn-SOD and Cu/Zn SOD protein levels were increased E-CDK2, cyclin A-CDK2, cyclin A-CDK1, and cyclin B-CDK1 [66,67]. It
without a loss of mitochondrial membrane potential or ROS production was discovered that luteolin controls the cell cycle.
after treating CH27 cells with 50 μM luteolin for 24 h [49]. Accordingly, Growth in the A549 lung cancer cell line was suppressed by luteolin
they hypothesized that the effect of luteolin on CH27 apoptosis can be by inducing G1 phase cell cycle arrest and apoptosis, accompanying the
attributed to its antioxidant effects [49]. percentage of cells in the S and G2/M phases decreased in comparison to
The p53 gene is a key tumor suppressor that suppresses tumor control cells following a 24 h exposure to luteolin (50 μM). This finding
development by binding to and regulating the expression of the p53 unequivocally demonstrates that luteolin induces a cell cycle arrest in
DNA-binding element in target genes [50]. Simultaneously, the p53 lung cancer cells [68]. When A549 cells were treated with 20 μM
gene exerts a positive regulatory effect on the pro-apoptotic gene Bax luteolin, the percentage of cells in the G2 phase increased 1.97-fold
while exerting a negative regulatory effect on the anti-apoptotic gene compared to the control. Further studies (western blot assay) demon
Bcl-2, thereby affecting the Bax/Bcl-2 ratio, which in turn regulates cell strated that the expression of G2 phase cell cycle-related proteins (cell
apoptosis [51]. It has been demonstrated that luteolin can regulate cycle protein A, p-CDC2, and p-Rb) was considerably lower in
miR-34a-5p by targeting MDM4 (a p53 regulator), which increases the luteolin-treated A549 cells. Consequently, by downregulating the
expression of p53, p21, and Bax proteins, activates caspase-3 and expression of G2 cell cycle-related proteins, luteolin causes G2 cell cycle
caspase-9, and triggers apoptosis in A549 and H460 cells [52]. arrest in NSCLC cells [69]. Generally, DNA-damaged cells must be
Furthermore, another in vitro experiment demonstrated that luteolin arrested to repair damage before replication. It was found that
also induces apoptosis in NSCLC cells by up-regulating p53 phosphor luteolin-treated cells exhibited significant DNA damage, and a study by
ylation, down-regulating PI3K, AKT, and MDM2 phosphorylation, sup Leung et al. found that luteolin also had an effect on the CH27 cell cycle,
pressing Bcl-2 expression, and up-regulating Bax expression [53]. These as evidenced by the induction of S-phase cell cycle arrest and increased
results suggest that luteolin may promote apoptosis in NSCLC cells by mRNA expression of DNA repair enzymes (human MutT homologue,
promoting p53 phosphorylation in A549 cells. Moreover, histone 8-oxoguanine-glycosylase, and apurinic endonuclease). However, when
deacetylase (HDAC) plays a crucial role in the cell cycle, differentiation, this severe DNA damage exceeded the capacity of the DNA repair en
and death. It serves as one of the epigenetic modifiers that control zymes, CH27 cells exhibited apoptosis after treatment with luteolin to
chromatin structure and gene expression. Since HDAC dysregulation eliminate the damaged cells [70]. Absent in melanoma 2 (AIM2) acts as
accelerates cancer growth, inhibitors targeting HDAC have proven to be a receptor for cell membrane DNA and helps protect against infection
highly effective therapeutics for various malignancies [54]. Luteolin is a and tissue damage by microbial or viral pathogens. Upon sensing cell
potent in vitro HDAC inhibitor that inhibits the acetylation of histones membrane DNA, AIM2 recruits the adaptor proteins ASC and
H3 and H4, leading to caspase-3/7 activation, DNA fragmentation, and procaspase-1 to form a functional inflammasome complex, which in
cell death [55]. In addition, sirtuins (sirt) have been described as duces the maturation and secretion of procaspase-1, thereby hydrolyz
NAD-dependent deacetylases involved in the regulation of apoptosis, ing the pro-inflammatory cytokine pro-IL-1β to its active form.
Moreover, AIM2 overexpression is linked to a poor prognosis and
4
Table 1
The pharmacological activity of luteolin in treatment of lung cancer.
Study Species (Sex, weight, n)/ Models Interventions Results Effects Neuroprotection Reference
types Cell line mechanism
In vivo Nude mice (female, NR, 7/ Lung cancer 30 mg/kg, [i.p.], ↓PD-L1, ↓STAT3, ↑IL-2 Induce apoptosis, inhibit Regulate immune Jiang et al.
and 8)/C57bl/6 J mice model NR; 10/20/30/ the tumor growth response 2021
in (female, NR, 7)/KRASLA2 40/50 μM
vitro mice (NR, NR, 7)/KRAS
mutation NSCLC (H460,
H358, A549) cells
In vivo SCID mice (female, NR, 7)/ Lung cancer 100 mg/kg, [p. ↓LIMK1, ↓Cyclin D1, Inhibit the proliferation of Pro-apoptotic; inhibit Zhang
and Human normal lung model o.], NR; 5/10/20/ ↓Cyclin D3, ↑Bax, lung cancer cells, induce cell proliferation et al. 2021
in epithelial cell (NL-20), 40 μM ↑Cleaved caspase 3, cell cycle arrest and
vitro lung cancer cell lines (NCI- ↑Cleaved caspase 7 apoptosis of lung cancer
H1975 and NCI-H1650) ↑Cleaved PARP, ↓Ki- cells
67, ↓p-LIMK1/2, ↓p-
Cofilin
In vitro NCI-H460 human lung Lung cancer 10/50/100/200/ ↑DR 4, ↑FasL, ↑Fas Induce growth inhibition Pro-apoptotic, Park et al.
carcinoma cells model 500 µM receptor, ↑Bax, ↑Bad, regulate autophagy 2013
↓Bcl-2, ↑Cytochrome c,
↓XIAP, ↑p-eIF2α,
↑CHOP, ↑p-JNK, ↑LC3II
In vitro The NSCLC cell line A549 Lung cancer 20/40/60/80 μM ↑JNK, ↑Bax, ↑Caspase- Increase apoptotic cells, Pro-apoptotic, inhibit Cai et al.
model 9, ↑Caspase-3, ↓NF-κB, increase G2 phase cells cell proliferation 2011
↓Cyclin A, ↓p-CDC2, ↓p-
Rb, ↓MEKK1
In vivo Nude mice (BALB/c nu/ Lung cancer 10/30 mg/kg, [i. ↑Cleaved caspase-3, Reduce the viability of Pro-apoptotic, inhibit Hong et al.
and nu) (male, 18–22 g, 6); model p.], 15 days; 1/5/ ↑PARP, ↑Bax, ↓Bcl-2, NCI-H1975 cells, increase cell migration 2014
in NCI-H1975, HCC827, NCI- 10/30/50/80/ ↓EGFR, ↓PI3K/Akt/ the number of apoptotic
vitro H820, A549, H9c2, L02, 100 μmol/L PTEN/mTOR, ↓CD34, cells, inhibit the migration
HEK293 cells ↓PCNA of NCI-H1975 cells
In vitro Human lung cancer A549 Lung cancer 10/25/50/75/ ↑Caspase-9, ↑Caspase- Induce cell growth Pro-apoptotic, inhibit Meng et al.
cells (CCL185), human model 100 µM 3, ↑Bax, ↓Bcl-2, ↑MEK- inhibition, reduce the cell migration 2016
non-transformed lung ERK, ↑E-cadherin, ↓N- percentage of viable cells
epithelial BEAS-2B cells cadherin
(CRL-9609)
In vivo BALB/cAnNCrj-nu/nu Lung cancer 10 mg/kg, [s.i.], ↑p38/ROS/caspase, Enhance cell death, radio- Pro-apoptotic, Cho et al.
and strain mice (NR, NR, 5)/ model 35 days; 10/20/ ↑Caspase-3, ↑Caspase- sensitization effect adjuvant therapy 2015
in The human NSCLC cell 30/40/50/ 8, ↑Caspase-9, ↓Bcl‑2
vitro lines, NCI-H1299 and 100 µM
-H460
In vitro NSCLC cell lines (A549 Lung cancer 5/10/20/30/ ↑Caspase-8, ↑Caspase- Induce cytochrome C Pro-apoptotic Wu et al.
and NCI–H1975), the model 40 μM 3, ↑Caspase-9, ↑DR5, release from mitochondria, 2020
human normal lung ↑p-Drp1, ↑Cytochrome decrease the ATP content
epithelial cell line Beas-2B c, ↑p-JNK and citrate synthase
activities
In vivo BALB/c nude mice (male, Lung cancer 50/100/200 mg/ ↑miR-34a-5p, Inhibit the proliferation of Pro-apoptotic Jiang et al.
and NR, 10)/Human NSCLC model kg, [i.g.], 15 days; ↑Caspase-3, ↑Caspase- cancer cells, inhibit tumor 2018
in A549 and H460 cells 5/10/20/30/40/ 9, ↑p53, ↑p21, ↓MDM4, growth
vitro 60/80/100 µM ↑Bax, ↓Bcl-2
In vitro The human lung cancer Lung cancer 40 μM ↑JNK, ↓MKP-1, ↑MKK7 Induce cellular superoxide Pro-apoptotic Bai et al.
cell lines H460 and A549 model accumulation 2012
In vitro CH27 cells - 50/80 μM ↓HSP27, ↑ORP150, Impair mitochondrial Pro-apoptotic Lee et al.
↑Caspase-4, ↑PDI, ↓p38 function 2010
In vitro Lung cancer cell lines H23, Lung cancer 1/10/20/40/ ↓NF-kB, ↑JNK, Potentiate cytotoxicity Pro-apoptotic Ju et al.
H2009, H460, and A549 model 80 µM ↑Caspase 3, ↑PARP, 2007
↑ROS, ↓SOD
In vivo Athymic (nu/nu) nude Lung cancer 20 mg/kg, [i.p.], 4 ↑Caspases-8, ↑Caspases- Inhibit tumor growth, Pro-apoptotic Yan et al.
and mice (male, NR, NR)/The model weeks; 2.5/5/ 9, ↑Caspases-3, ↑PARP cause disruption of normal 2012
in NSCLC cell line (A549) 10 µM compact architecture of
vitro and a cervical cancer cell tumor tissue
line (HeLa)
In vitro The NCI-H460 human lung Lung cancer 20/40/80/ ↑Bax/Bcl-2, ↓Sirt1 Cause an accumulation of Pro-apoptotic Ma et al.
carcinoma cell line, HEK- model 160 µM cells in the S phase, inhibit 2015
293 T cell line the migration of the NCI-
H460 cells
In vivo Athymic NMRI nude mice Lung cancer 20 mg/kg, [i.p.], ↑Caspase 3, ↑Caspase 7, Reduce cellular migration, Pro-apoptotic Attoub
and (nu/nu) (female, NR, 6/ model 18 days; 1/10/25/ ↓H3 and H4 HDAC impair the invasion of et al. 2011
in 7)/Human lung cancer 50/100/200 µM activities LNM35 cells, reduce the
vitro cells LNM35 growth of LNM35 human
tumor xenografts,
potentiate the cytotoxic
effect of cisplatin
In vitro The human lung squamous Lung cancer 30/50/80 μM ↓DPPH, ↑SOD, Induce CH27 cell apoptosis Pro-apoptotic Leung et al.
carcinoma cell line CH27 model ↑Catalase 2006
(continued on next page)
5
Table 1 (continued )
In vivo BALB/c nude mice (male, Lung cancer 30 mg/kg, NR, 25 ↑Bax, ↑Cleaved-caspase Hinder cell viability, Pro-apoptotic Zheng
and NR, 6)/Human lung cancer model days; 25/50/ 3, ↓Bcl2, colony formation, et al. 2023
in cell lines H460 and A549 100 μM ↑circ_0000190, ↓miR- migration, invasion, and
vitro cells 130a-3p, ↓Notch-1, promote apoptosis of lung
↓Hes-1, ↓VEGF cancer cells, repress tumor
growth
In vitro The human NSCLC cell Lung cancer 0.4/0.8/1.6/3.2/ ↓p-PI3K, ↓p-Akt, ↓p- Increase apoptosis rate of Pro-apoptotic Ye et al.
lines A549 and H1299, the model 6.4 mg/mL MDM2, ↑p-P53, ↓Bcl-2, A549 cells 2023
normal human lung ↑Bax
epithelial cell line BEAS-
2B
In vitro Human lung Lung cancer 20/40/60 μM ↑Bax, ↓Bcl-xl, ↓Bcl-2, Inhibit the growth of A549 Pro-apoptotic Chen et al.
adenocarcinoma cells model ↑Caspase-9, ↑Caspase- cell lines, arrest the cell 2012
A549 3, ↑PARP cycle progression in A549
cells
In vitro The murine macrophage Lung cancer 1/5/10/20/30 µM ↓p-STAT6, ↓Arginase-1, Suppress the M2-like Inhibit the migration Choi et al.
cell line, RAW 264.7 cell, model ↓MRC1, ↓CCL2 tumor-associated 2016
the human acute macrophages phenotype,
monocytic leukemia cell suppress monocytes
line, THP-1 cell, the migration, inhibit
murine Lewis lung proliferation and migration
carcinoma cell line of lung carcinoma cells,
suppress the growth of
Lewis lung cancer cells
In vitro Lung carcinoma cell line Lung cancer 30/50/80 µM ↑Apurinic Induce CH27 cells S-phase Inhibit cell Leung et al.
CH27 model endonuclease, arrest, induce CH27 cells proliferation, pro- 2005
↑Apoptosis-inducing nuclear morphological apoptotic
factor protein change, DNA condensation
and apoptosis
In vitro Balb/c nude mice (male, Lung cancer 150 mg/kg, [p. ↓Androgen receptor Inhibit the growth of A549 Inhibit cell Li et al.
NR, 10)/The human lung model o.], 28 days; 5/ xenogeneic tumors proliferation and 2023
cancer cell lines PC9, 10/20/40/80 µM migration
A549, and H460
In vitro The human lung Lung cancer 1/10/50 µM ↓Claudin-2, ↑p-ERK1/2, Inhibit of binding of STAT3 Inhibit cell Sonoki
adenocarcinoma A549 cell model ↑c-Fos on the promoter region of proliferation et al. 2017
line claudin-2
In vivo Swiss albino mice (male, B(a)P induced 15 mg/kg, [p.o.], ↓CEA, ↓NSE, ↑SOD, Reduce the alveolar Inhibit cell Kasala
18–22 g, 6) lung 16 weeks ↑CAT, ↑GPx, ↑GR, damage proliferation et al. 2016
carcinogenesis ↑GST, ↑GSH, ↑Vitamin
E, ↑Vitamin C, ↓PCNA,
↓CYP1A1, ↓NF-kB
In vitro The A549 and H460 cells Lung cancer 20/40/80 µM ↓TAM RTKs, ↓Tyro3, Inhibit proliferation of Inhibit cell Lee et al.
model ↓Axl, ↓MerTK, ↑p21 both parental and proliferation 2017
cisplatin-resistant non-
small lung cancer cells,
increase the cytotoxicity of
the cisplatin-resistant cells
In vitro A549 cells Lung cancer 25/50 µM ↑JC-1 green/red Increase the cells in G1 Inhibit cell migration Zhao et al.
model fluorescence phase and decrease the and proliferation 2011
cells in S and G2/M phases,
induce apoptosis in tumor
cells, induce mitochondrial
disruption
In vivo Nude mice (BALB/c nu/ Lung cancer 50 mg/kg, [i.p.], ↓Cyclin B1, ↑p21, ↑p- Suppress the proliferation Inhibit cell migration Yu et al.
and nu) (male, 18–22 g, 5)/ model NR; 2.5/5/10/20/ Cdc2, ↓Vimentin, of NSCLC cells, induce G2/ and invasion, inhibit 2019
in Cell lines A549, H460, 40/80 μM ↓MMP9, ↑E-cadherin, M phase arrest, suppress cell proliferation
vitro H226, and 16HBE ↓AIM2, ↓Pro-caspase-1, migratory ability, decrease
↓Caspase-1 p10, ↓Pro- invasiveness, inhibit
IL-1β, ↓IL-1β, ↓PCNA growth of xenografts,
decrease the volume and
weight of tumors
In vitro MRC-5 human lung Lung cancer 5/10/20/40/50/ ↓p-FAK, ↓p-Src, ↓Rac1, Attenuate migration and Inhibit cell migration Masraksa
fibroblast cells and A549 model 80 μM ↓Cdc42, ↓RhoA invasion of lung cancer and invasion et al. 2020
human lung carcinoma A549 cells, attenuate
cells filopodia formation of lung
cancer A549 cells, suppress
migration-related protein
expression
In vitro The human Lung cancer 10/40 µM ↑E-cadherin, ↓N- Reduce the interaction Inhibit cell migration Chen et al.
adenocarcinoma cell line model cadherin, ↓Snail, ↑IkB- between Snail and the E- and invasion 2013
A549, the A549- α, ↓NF-kB, ↓PI3K/Akt cadherin promoter
p53shRNA cell lines, the
H460, CL1–0 and CL1–5
cells
(continued on next page)
6
Table 1 (continued )
In vitro Human A549 and NCI- Lung cancer 5/10/25/50 µM ↑E-cadherin, ↑ZO-1, ↓N- Inhibit hypoxia-induced Inhibit cell migration Ruan et al.
H1975 (H1975) NSCLC model cadherin, ↓Claudin-1, cell adhesion, proliferation and invasion 2012
cells ↓β-Catenin, ↓Snail, and motility
↓Vimentin, ↓Integrin
β1, ↓FAK
In vitro NSCLC H460 cells Lung cancer 7.5/12.5/15/25/ ↓MMP-2, ↓ICAM-1, Reduce cell migration, Inhibit cell migration Lin et al.
model 30/50/100/ ↓EGFR, ↓p-PI3K, ↓p-Akt reduce metastatic 2022
200 μM progression
In vivo C57BL/6 mice (male, Lung cancer 20 mg/kg, [i.g.], ↓TNF‑α, ↓IL‑6, Protect skeletal and heart Improvement of Chen et al.
18–22 g, 10) model 17 days ↓MuRF1, ↓Atrogin-1, muscle from cancer- cancer complications 2018
↓IKKβ, ↓p‑p65, ↓p-p38 induced wasting and loss
In vivo C57BL/6 mice (male, NR, LLC-induced 1/10/50 mg/kg, ↓p38 MAPK, ↓GFAP, Ameliorate Lewis lung Improvement of Zhou et al.
and 6)/The murine Lewis lung BCP mouse [i.p.], 8 days; ↓IBA1, ↓NLRP3, ↓ASC, cancer-induced bone pain, cancer complications 2022
in cancer cell line model 0.01/0.1/1 mg, [i. ↓Caspase1, ↓IL-1β prevent bone cancer pain-
vitro t.], 8 days; 5 mg/ induced glial activation
mL
In vitro The human lung cancer Lung cancer 5/10/20/40 µM ↓NF-κB, ↓Bcl-XL, Sensitize SMC3’s Adjuvant therapy, Bai et al.
cell line H23 model ↓MnSOD, ↑Caspase-8, anticancer activity, pro-apoptotic 2009
↑Caspase-3, ↑PARP enhance cytotoxicity in
cancer cells
In vivo Athymic nu/nu nude mice Lung cancer 10/20/40/60/ ↓Nrf2, ↓NQO1, ↓HO-1, Inhibit the growth of Adjuvant therapy Chian et al.
(female, 20–22 g, 6) model 80 mg/kg, [i.g.], ↓GSH xenograft tumors, enhance 2014
35 days the toxic effect of cisplatin,
reduce tumor weight
In vitro Human normal lung Lung cancer 1/10/25/50/100/ ↓MET, ↓p-MET, ↓p-Akt, Increase sensitivity, inhibit Adjuvant therapy Huang
epithelial Beas-2B cell line, model 150 µM ↓HGF the proliferation, inhibit et al. 2023
the human NSCLC cell line the migration and invasion
H1975 with EGFR L858R of the acquired
and T790M mutations Osimertinib-resistant cell
line
In vitro A549 NSCLC cell lines Lung cancer 1/3/5/6/9/10/ ↓Nrf2, ↓HO-1, ↓NQO1, Promote Nrf2 mRNA Adjuvant therapy Tang et al.
model 12/18/20/24 µM ↓GSH degradation, reduce 2011
resistance to the anticancer
drugs oxaliplatin,
bleomycin, and
doxorubicin in A549 cells
In vivo Albino Wistar rats (male, - 50/100 mg/kg, ↓LPO, ↑CAT, ↑SOD, Enhance survivability, Adjuvant therapy Owumi
155–165 g, 10) [p.o.], 14 days ↑GPx, ↑GST, ↑GSH, mean body weight and et al. 2021
↓TNF-α, ↓IL-1β, organo-somatic indices,
↓Caspase-3, ↑IL-10 increase the blood level of
platelets and plateletcrit
Abbreviations:
AIM2, Absent in melanoma 2; Akt, Protein kinase B; CAT, Catalase; CCL2, Chemokine (CeC motif) ligand 2; Cdc42, Cell division control protein 42; CEA, Carci
noembryonic antigen; CHOP, C/EBP homologous protein; CYP1A1, Cytochrome P450 1A1; DR5, Death receptor 5; Drp1, Dynamin-related protein 1; EGFR, Epidermal
growth factor receptor; eIF2α, Eukaryotic initiation factor 2α; ERK, Extracellular signal-regulated kinase; FAK, Focal adhesion kinase; GPx, Glutathione peroxidase; GR,
Glutathione reductase; GSH, Glutathione; GST, Glutathione S-transferase; HDAC, Histone deacetylase; HGF, Hepatocyte growth factor; HO-1, Heme oxygenase-1;
Hsp90, Heat shock protein 90; i.g., Intragastrical; i.p., Intraperitoneal; i.t., Intrathecally; ICAM-1, Intercellular adhesion molecule; IKK, IκB kinase; IL, Interleukin;
JNK, c-Jun N-terminal kinase; LC3 I/II, Light chain 3 I/II; LIMK 1, LIM domain kinase 1; LPO, Lipid peroxidation; MET, Mesenchymal-epithelial transition factor; MKK,
Mitogen-activated protein kinase kinase; MKP, Mitogen-activated protein kinase phosphatase; MMP 2, Metalloproteinase-2; MnSOD, Manganese superoxide dis
mutase; MRC1, Mannose receptor C type 1; NF-κB, Nuclear factor-kappaB; NLRP3, NOD-like receptor family pyrin domain containing 3; NQO1, NADPH quinone
oxidoreductase 1; NR, No report; Nrf2, Nuclear factor erythroid 2-related factor 2; NSCLC, Non-small cell lung cancer; NSE, Neuron specific enolase; ORP150, 150 kDa
oxygen-regulated protein; p.o., Oral gavage; p38MAPK, p38 Mitogen-activated protein kinase; PARP, Poly (ADP-ribose) polymerase; PCNA, Proliferating cell nuclear
antigen; PDI, Protein disulfide isomerase; PI3K, Phosphatidylinositol 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; ROS, Reactive oxygen species; RTKs,
Receptor tyrosine kinases; s.i., Subcutaneously inject; SCID mice, Severe combined immunodeficient mice; SMC3, Smac mimetic compound 3; Src, Non-receptor
tyrosine kinase; STAT6, Signal transducer and activator of transcription 6; TNF-α, Tumor necrosis factor-α; VEGF, Vascular endothelium growth factor; XIAP, X
chromosome encoded inhibitor of apoptosis protein
increases lung inflammation [71,72]. It was found that luteolin signifi kinase activity of LIMK1 by targeting LIMK1, reduced the expression of
cantly reduced the mRNA expression levels of AIM2, caspase-1, and cell cycle protein D1 by down-regulating LIMK1 signaling-related tar
IL-1β, thereby inhibiting the activation of the AIM2 inflammasome. gets (including p-LIMK and p-cofilin), and induced cell cycle arrest in the
Lutein markedly suppressed the proliferation of NSCLC cells by upre G1 phase in NCI-H1975 and NCI-H1650 cells. Moreover, luteolin
gulating p21 expression, blocking the G2/M transition in A549 and treatment (20 or 40 μmol/L) significantly inhibited the proliferation of
H460 cells, inducing G2/M phase arrest, and reducing the expression of lung cancer cells in a time-dependent manner [11]. Proliferating cell
cell cycle protein B1 [72]. These investigations demonstrated that nuclear antigen (PCNA), an acidic nuclear protein found in eukaryotes,
luteolin-induced arrest occurred in the lung cancer cell cycle during the is a cyclic homotrimer that acts as a co-protein for DNA polymerase δ
G1, S, G2, and M phases. and coordinates DNA replication. PCNA is associated with the cell cycle,
Additionally, luteolin inhibits tumor cell proliferation through exhibiting minimal expression during the G0 phase, which increases
alternative mechanisms. LIM structural domain kinase (LIMK) 1, a during the G1 phase, peaks during the S phase, and decreases during the
member of the serine/threonine kinase family, is significantly expressed G2-M phase [74,75]. PCNA expression can serve as an indicator of cell
in a variety of malignancies [73]. Luteolin significantly inhibited the proliferation status [76]. Additionally, western blot analysis revealed
7
Fig. 4. Luteolin promotes apoptosis in lung cancer cells. Luteolin can promote apoptosis by up-regulating the expression of JNK and p53, inducing ROS accumu
lation, activating caspase-3 and caspase-9, inducing the release of Cyt c, increasing Bax expression, and decreasing Bcl-2 expression. Akt, Protein kinase B; APAF1,
Apoptotic protease-activating factor 1; Bcl-2, B cell lymphoma-2; Cyt c, Cytochrome c; ERK, Extracellular signal-regulated kinase; FADD, Fas associated death
domain; FasLR, Fas ligand receptor; FGF2, Fibroblast growth factor 2; IGF-1, Insulin-like growth factor-1; JNK, c-Jun N-terminal kinase; MKP-1, MAPK phosphatase-
1; NF-κB, Nuclear factor-kappa B; PI3K, Phosphatidylinositol 3 kinase; ROS, Reactive oxygen species; RTK, Receptor tyrosine kinases; tBID, Truncated BID; TGF-α,
Transforming growth factor α; TRADD, TNF-α receptor 1-associated death domain protein; TRAIL, TNF-related apoptosis-inducing ligand receptor; XIAP, X-linked
inhibitor of apoptosis protein (Made with Figdraw).
that luteolin suppressed the up-regulation of PCNA protein [72,74]. inhibited tumor cell proliferation through a mechanism involving
Furthermore, claudin-2 is produced in the tight junctions of the leaky inhibiting the G1, S, G2, and M phases of the lung cancer cell cycle, as
epithelia, where it forms water-permeable and cation-selective para well as by regulating the expression of tumor proliferation-associated
cellular channels. The expression of claudin-2 is dysregulated in factors such as LIMK, PCNA, claudin-2, AR, and TAM RTKs, among
numerous diseases, including fibrosis, inflammation, and malignancy. others (Fig. 5).
Claudin-2 regulates the G1/S transition in lung cancer cells through the
cell cycle proteins D1 and E1 [77]. Previous studies have shown that
claudin-2 knockdown decreases cell proliferation [78]. By preventing 5.3. Inhibition of cell migration and invasion
STAT3 from attaching to the claudin-2 promoter region in A549 cells,
luteolin (50 µM) decreased claudin-2 production and cell proliferation Tumor metastasis is the primary cause of lethality in cancer [83].
in A549 cells [78]. Androgen receptors (AR) are ligand-activated nu Malignant tumor cells spread from the original lesion to distant loca
clear transcription factors belonging to the steroid hormone receptor tions, where they continue to grow and proliferate until eventually
family that regulate the transcriptional activity of genes involved in forming the same type of tumor as the original lesion [84,85]. Pre
escaping apoptosis and inducing cell proliferation [79]. By binding to venting tumor cells from spreading to other areas of the body by
the phosphorylation site of AR, Thr (877), luteolin (80 μM) was revealed inhibiting tumor metastasis can therefore postpone tumor progression
to decrease AR protein expression in the lung cancer cell line A549 and [86]. The accelerated migration and invasion of lung cancer cells
to dose-dependently reduce A549 cell proliferation by down-regulating induced by the epithelial-mesenchymal transition (EMT) plays a key role
AR expression [80]. Furthermore, the receptor tyrosine kinases (RTKs) in the metastasis of these cells [87]. EMT is characterized by the
belonging to the TAM family (TYRO3, AXL, and MERTK) may be tar disruption of intercellular tight junctions and cell polarity, resulting in
geted therapeutically in a range of malignancies. TAM RTK stimulates weakened intercellular adhesion and enhanced cell motility to move
signaling pathways in cancer cells that support the ability of the cells to freely in the interstitial matrix. In addition to this, the expression of the
metastasize, survive, and resist various chemotherapeutic drugs and epithelial cell marker protein E-cadherin is down-regulated while the
targeted treatments [81]. Luteolin also inhibits the growth of NSCLC expression of mesenchymal cell marker proteins, including vimentin,
cells by lowering the protein levels of all three TAM RTKs in A549 cells fibronectin, and N-cadherin, is up-regulated, resulting in a loss of po
in a dose-dependent manner [82]. larity in epithelial cells and their transformation into a mesenchymal
In conclusion, these studies demonstrated that luteolin significantly phenotype [88]. EMT is regulated by multiple signaling pathways, with
the transforming growth factor β (TGF-β)/Smads signaling pathway
8
Fig. 5. Luteolin inhibits tumor cell proliferation. Luteolin inhibits the proliferation of tumor cells by inhibiting the G1, S, G2, and M phases of the lung cancer cell
cycle. CDK, Cyclin-dependent kinase (Made with Figdraw).
being a key driver [89]. This leads to a decrease in the expression of the control the actin cytoskeleton and cell movement, was altered by
epithelial marker E-cadherin and an increase in the expression of the luteolin (20–40 μM) [12]. Ruan et al. revealed that luteolin inhibited
mesenchymal markers [89,90]. The PI3K/AKT signaling pathway trig hypoxia-induced EMT in NSCLC cells, as evidenced by an increase in
gers the activation of the mTOR complex and NF-κB, which promotes the E-cadherin expression and a decrease in N-cadherin and vimentin
development of EMT in tumor cells [91]. The Wnt/β-Catenin signaling expression. Subsequent investigations demonstrated that luteolin sup
pathway is crucial for controlling epithelial cell phenotypic character pressed the expression of integrin β1 and FAK in hypoxic A549/H1975
istics, cellular connection, and tissue homeostasis throughout the EMT cells, with an up-regulation of E-cadherin coupled with a
process in malignancies. Tumor EMT transpires with the activation of down-regulation of integrin β1 and FAK [96]. Based on these in
this pathway [92]. vestigations, luteolin at least partially prevents hypoxia-induced EMT by
Luteolin exerts anticancer activity by inhibiting EMT, and the suppressing integrin β1-FAK/Src expression. Furthermore, luteolin pre
possible mechanisms include the inhibition of the EGFR-PI3K-AKT and vented EMT by triggering the MEK/ERK signaling pathway, which
integrin β1-FAK/Src signaling pathways and activation of the MEK/ERK markedly raised the levels of E-cadherin and decreased those of N-cad
signaling pathway. Pretreatment with luteolin (10 μM) significantly herin [97].
blocked PI3K/Akt pathway activation, prevented NF-kB binding to the In addition, AR, AIM2, and chemokine (C-C motif) ligand 2 (CCL2)
Snail promoter region, disrupted the interaction between Snail and the have important roles in luteolin-mediated EMT and cell migration in
E-cadherin promoter, restored E-cadherin expression, and slowed down hibition. 80 μM luteolin significantly reduced the proliferation and
TGF-β1-induced EMT in lung cancer cells [93]. Subsequent research migration of A549 cells, which was achieved through the down-
showed that luteolin significantly inhibited the growth of regulation of the androgen receptor [80]. By reducing the expression
erlotinib-resistant NSCLC harboring the mutated EGF receptor of vimentin and MMP9 and raising that of E-cadherin, luteolin can
L858R/T790M by blocking the attachment of Hsp90 to the mutant EGF significantly inhibit EMT in A549 and H460 cells, which inhibits the
receptor. This prevented PI3K/Akt/mTOR signaling as well as ability of the cells to migrate and invade. When AIM2 was absent, the
NCI-H1975 cell migration [94]. Similarly, Lin et al. revealed that negative regulatory effect of luteolin on EMT in A549 and H460 cells
luteolin (0, 5, 10, or 20 μM) reduced the expression of pro-metastatic was nearly completely eliminated, suggesting that AIM2 may be a po
factors (e.g., pro-MMP-2 and ICAM-1) in human lung cancer H460 tential target of luteolin in inhibiting EMT [72]. In addition, CCL2 is one
cells by inhibiting the EGFR-PI3K-AKT pathway and decreased cell of the key chemokines that regulate monocyte migration and infiltra
migration capacity [95]. Masraksa et al. found that luteolin significantly tion. Luteolin inhibits the M2-like tumor-associated macrophage (TAM)
blocked the migration and invasion of lung cancer cells in a phenotype by decreasing CCL2 production, which reduces the recruit
concentration-dependent manner. In addition to stimulating several ment of monocytes and Lewis lung carcinoma cell migration [98].
downstream targets such as the ras homolog gene family member A In summary, these studies demonstrated that luteolin has a positive
(RhoA) pathway, cell division control protein 42 (Cdc42), and the effect on inhibiting tumor EMT and migration by inhibiting the EGFR-
ras-related C3 botulinum toxin substrate 1 (Rac1), FAK-Src can mediate PI3K-AKT and integrin β1-FAK/Src signaling pathways, activating the
cellular transformations, including uncontrolled cell division [12]. MEK/ERK signaling pathway, and regulating the expression of
Treatment of A549 cells with luteolin (20–40 μM) markedly inhibited migration-related factors such as AR, AIM2, and CCL2, among others
the expression of activated focal adhesion kinase (FAK) and activated (Fig. 6).
non-receptor tyrosine kinase (Src), limiting NSCLC cell migration in
vitro. Additionally, the expression of RhoA, Cdc42, and Rac1, which
9
Fig. 6. Luteolin inhibits tumor cell invasion and metastasis. Luteolin inhibits EMT to suppress tumor cell invasion and metastasis. The main mechanisms involved
include the inhibition of the EGFR-PI3K-Akt and integrin β1-FAK/Src signaling pathways. Akt, Protein kinase B; EGFR, Epidermal growth factor receptor; EMT,
Epithelial-mesenchymal transition; ERK, Extracellular signal-regulated kinase; FAK, Focal adhesion kinase; mTOR, Mechanistic target of rapamycin; NF-κB, Nuclear
factor-kappa B; PI3K, Phosphatidylinositol 3 kinase; Src, Non-receptor tyrosine kinase; TGF-βR, Transforming growth factor β receptor (Made with Figdraw).
5.4. Application of luteolin in adjuvant therapy During a state of oxidative stress or exogenous substance stimulation,
intracellular ROS increases, disrupting the degradation mechanism of
Lung cancer is the most prevalent malignant tumor in the world, with Nrf2, and elevated Nrf2 levels can induce the transcription of a series of
NSCLC accounting for approximately 85 % of lung cancers [99]. Surgery antioxidant response element (ARE) response genes, leading to the
is the preferred intervention for patients with early and intermediate activation of cellular defenses, increasing antioxidant capacity, and thus
NSCLC once diagnosed; however, owing to the lack of obvious symp contributing to the development of tumor malignant processes and drug
toms during the early stages of NSCLC, most patients are already in the resistance [99,104]. The Nrf2 signaling pathway and tumor growth in
middle or late stages when diagnosed and miss the opportunity for vivo were found to be suppressed by luteolin, and the combination of
radical treatment by surgery. Therefore, chemotherapy has become the luteolin and cisplatin was found to be more effective in reducing tumor
primary treatment for late-stage NSCLC; however, it can cause serious cell growth than when either compound was administered alone. Sub
adverse effects, resulting in a decline in the quality of life of the patients sequent mechanistic research revealed that luteolin accelerated the
[100]. Additionally, radiotherapy serves as an important method to degradation of Nrf2 mRNA, which resulted in a substantial decrease in
prolong the survival of patients with lung cancer, including radical Nrf2 levels (RNA and protein), a reduction in Nrf2 binding to the ARE, a
radiotherapy for patients with limited stage disease, local radiotherapy, decrease in the expression of ARE driver genes, and a depletion of
and brain prophylactic radiotherapy for patients with extensive stage reduced glutathione [16]. Similarly, Nrf2 inhibition by luteolin resulted
disease. However, owing to a variety of factors, including tumor load in negative regulation of the Nrf2/ARE pathway and sensitization of
and growth kinetics, tumor heterogeneity, tumor microenvironment, human lung cancer A549 cells to therapeutic agents in a study by Tang
and the body’s immune system, patients may experience insensitivity or et al. Luteolin (10 μM) caused dose-dependent reductions in the
resistance during treatment [101,102]. expression of the Nrf2 target genes AKR1C1, NQO1, HO-1, GCLC, and
In terms of improving this challenge, luteolin acts as a sensitizer to MRP2. The binding of Nrf2 to the ARE sites in the promoters of NQO1
chemotherapeutic drugs and radiation therapy in lung cancer cells. First, and HO-1 was markedly decreased by luteolin (20 μM). Moreover, the
luteolin prevented nuclear factor E2 p45-related factor 2 (Nrf2), a IC50 values of anticancer medications, such as oxaliplatin, bleomycin,
crucial transcription factor in cellular defense against oxidative stress, and doxorubicin, were reduced by half from 120 μM, 100 μM, and
from mediating chemotherapeutic drug resistance [103]. Nrf2 is pri 2 μg/mL to 60 μM, 59 μM, and 1 μg/mL, respectively, following luteolin
marily negatively regulated by Keap1. Furthermore, Nrf2 is located in treatment. This resulted in an increase in the susceptibility of cancer
the cytoplasm in the presence of the regulatory protein Keap1, which cells to chemotherapeutic treatments [105]. These investigations indi
binds with Nrf2 and functions as an articulating protein. This interaction cate that luteolin can be utilized as a natural chemotherapeutic sensi
allows Nrf2 to be sequentially broken down by the proteasome in tizer. Second, by targeting the HGF-MET-Akt pathway, luteolin aids
ubiquitin-mediated mechanisms that maintain Nrf2 at low levels. NSCLC cells in overcoming their acquired resistance to osimertinib.
10
Because patients with NSCLC have the EGFR T790M mutation, osi In conclusion, these studies indicate that luteolin has a sensitizing
mertinib, a third-generation epidermal growth factor receptor tyrosine effect on chemotherapeutic drugs and radiation therapy, and the
kinase inhibitor (EGFR-TKI), can effectively treat their acquired resis mechanism involves inhibiting the activation of Nrf2 and the HGF-MET-
tance to first- and second-generation EGFR-TKIs [99]. However, ac Akt signaling pathway, which also plays an important role in alleviating
quired resistance to osimertinib continues to be a significant clinical the adverse effects of chemotherapeutic drugs and radiosensitization.
obstacle. By inhibiting the HGF-MET-Akt pathway, luteolin and osi This highlights the clinical potential of incorporating luteolin in com
mertinib can work synergistically to overcome acquired osimertinib bination therapy for lung cancer patients with acquired drug resistance
resistance, which is caused by MET amplification and overactivation. (Fig. 7).
This suggests combined treatment with luteolin and osimertinib holds
clinical potential for treating acquired resistance in patients with NSCLC 5.5. Improvement of cancer complications
[106]. Furthermore, these findings underscore that luteolin and its de
rivatives should be investigated further to overcome acquired resistance Cancer cachexia is a complex metabolic syndrome associated with
to osimertinib and other potential EGFR-TKIs. cancer, characterized by the progressive depletion of adipose and mus
Furthermore, luteolin serves as a radiosensitizer in NSCLC cells. For cle tissue, weight loss, loss of appetite, early satiety, malaise, and
example, in NCI-H460 cells, the combination of 20 µM luteolin and weakness due to metabolic changes caused by tumor load and cytokines
γ-ionizing radiation increased the rate of apoptosis by approximately [108–110]. Therefore, the prevention and treatment of cancer cachexia
48 % compared to γ-ionizing radiation alone and by approximately has emerged as a crucial factor for the multidisciplinary, comprehensive
23 % compared to 20 µM luteolin only. This effect may be achieved treatment of tumors and has received widespread attention [111]. The
through the activation of the p38/ROS/caspase cascade [15]. Finally, pathogenesis of carcinomatous cachexia is complex and has not yet been
luteolin also plays a key role in attenuating the adverse effects of satisfactorily elucidated. The current understanding of carcinomatous
chemotherapeutic agents. Doxorubicin is a broad-spectrum and highly cachexia posits that it is caused by tumor factors, body factors, and the
effective anthracycline anti-tumor agent widely used in clinical settings; interaction between the tumor and the body [112]. Inflammatory fac
however, its use has been limited because of its adverse effects [107]. tors such as TNF-α, IL-6, IL-1, and INF-γ play a central role in the
Combining luteolin and doxorubicin decreases apoptotic biomarkers pathophysiology of cancer cachexia, and inhibiting the synthesis and
and pro-inflammatory cytokines, boosts platelet, white blood, and red activity of these cytokines could serve as a strategy for the treatment of
blood cell counts, and reduces the toxicity of doxorubicin in the hema cachexia [113]. Skeletal muscle atrophy is the most prominent clinical
tological system and lungs. Moreover, supplementing patients receiving manifestation of cancer cachexia [111]. Additionally, the expression of
doxorubicin treatment with phytochemicals with antioxidant activity, MuRF1 and atrogin-1 is strongly up-regulated during cachexia;
especially luteolin, may prevent unintentional adverse effects in the atrogin-1 is a ubiquitin ligase that mediates structural muscle proteolysis
lungs and hematological system [13]. and inhibits protein synthesis, while MuRF1 promotes the
Fig. 7. Luteolin adjuvant radiotherapy and chemotherapy. Luteolin inhibits Nrf2-mediated chemoresistance and overcomes acquired resistance to osimertinib
caused by MET amplification and hyperactivation; luteolin also has radiosensitizing effects by activating the p38/ROS/caspase pathway. Akt, Protein kinase B; ARE,
Antioxidant response element; Cyt c, Cytochrome c; EGFR, Epidermal growth factor receptor; EMT, Epithelial-mesenchymal transition; ERK, Extracellular signal-
regulated kinase; KEAP1, Kelch-like ECH-associated protein 1; mTOR, Mechanistic target of rapamycin; NRF2, Nuclear factor E2 p45-related factor 2; p38MAPK,
p38 Mitogen-activated protein kinase; PI3K, Phosphatidylinositol 3 kinase; ROS, Reactive oxygen species (Made with Figdraw).
11
ubiquitination of thick myofilaments [114,115]. During catabolism, Akt that luteolin inhibits the activation of the NF-κB and p38 MAPK
activity is reduced, mTOR downstream of Akt is affected, and the protein signaling pathways, thereby suppressing the inflammatory response.
synthesis pathway is inhibited. Consequently, the down-regulation of Based on this, luteolin could be a potential safe and efficient alternative
Akt triggers the dephosphorylation of FOXO proteins followed by nu therapy for the treatment of cancer cachexia and malignant bone pain
clear translocation, which promotes the transcription of MuRF1 and (Fig. 8).
atrogin-1, which in turn promotes myofibrillar protein degradation and
induces muscle atrophy [116]. Transcription factors such as NF-κB and 5.6. Immune response regulation
STAT3 are also involved in the regulation of atrogin-1 [114,117]. IκB
kinase (IKK)-β activation is significantly influenced by p38 MAPK ac Surgery remains the only viable treatment option for potentially
tivity [118]. Therefore, p38 MAPK is also implicated in the regulation of curable patients; however, many patients with NSCLC are no longer
inflammation and cancer. eligible for surgery by the time of detection, and many patients with
The action of luteolin on cancer-associated inflammation and resected lung cancer suffer from disease recurrence [121]. Although
cachexia has been demonstrated. It prevented the depletion and loss of chemotherapy can prolong the short-term survival of patients, it has
skeletal and cardiac muscle in vivo caused by cancer, reduced lung greater adverse effects and a poorer survival prognosis [122]. Recently,
cancer-induced bone pain, and decreased the inflammatory response by utilizing immunotherapy for tumors has garnered substantial interest
inhibiting the activation of the NF-κB and p38 MAPK signaling path following the development of molecular-targeted therapy and immune
ways. In a cancer cachexia model, Chen et al. discovered that luteolin checkpoint inhibitors, a type of immunotherapy that targets the immune
reduced the generation of the inflammatory mediators TNF-α and IL-6 escape mechanism, which has instilled new hope in many patients with
and suppressed MuRF1 expression by lowering NF-κB activation at the advanced lung cancer [100]. Physiologically, the immune system relies
transcriptional and translational levels. Furthermore, luteolin reduces on multiple immune checkpoints, including CTLA-4 and PD-1, to avoid
p38 expression, which mitigates the effects of atrogin-1 overexpression. autoimmune diseases caused by excessive immune responses [123,124].
Luteolin protects skeletal and cardiac muscle from cancer-induced CTLA-4 is primarily expressed in T cells, and it can competitively inhibit
depletion and loss in vivo by down-regulating the expression of genes the binding of CD28 to CD80/CD86, thereby blocking the secondary
associated with muscle proteolysis [119]. Zhou et al. revealed that signals of T cell activation and achieving immune tolerance [125]. PD-1
luteolin alleviated bone cancer pain in a Lewis lung cancer mouse model is a type I transmembrane protein that is mostly expressed in macro
in a dose-dependent manner. Luteolin inhibited neuroinflammation in phages, B-lymphocytes, dendritic cells, monocytes, tumor-specific acti
the spinal dorsal horn by suppressing p38 MAPK phosphorylation to vated T-cells, myeloid cells, and natural killer (NK) cells with two known
inhibit glial cell activation (GFAP and IBA1), suppressed the production ligands (PD-L1 and PD-L2) [126–129]. Tumor progression may be
of NOD-like receptor family pyrin domain containing 3 (NLRP3) in attributed to the development of some effective mechanism to evade this
flammatory vesicles (NLRP3, ASC, caspase-1, and IL-1β), and alleviated immune system surveillance. One such mechanism involves the upre
lung cancer-induced bone pain [120]. Therefore, these studies indicate gulation of the inhibitory ligand PD-L1 by tumor cells, which binds to
Fig. 8. Luteolin alleviates cancer complications. Luteolin suppresses inflammatory responses and ameliorates cancer complications by inhibiting the activation of the
NF-κB and p38 MAPK signaling pathways. IGF-1, Insulin-like growth factor-1; Akt, Protein kinase B; PI3K, Phosphatidylinositol 3 kinase; mTOR, Mechanistic target of
rapamycin; FOXO, Forkhead box O; IL, Interleukin; JAK, Janus kinase; STAT3, Signal transducer and activator of transcription 3; NF-κB, Nuclear factor-kappa B; TNF-
α, Tumor necrosis factor-α; p38MAPK, p38 Mitogen-activated protein kinase; IKKβ, IκB kinase β; NF-κB, Nuclear factor-kappa B (Made with Figdraw).
12
the anti-tumor T-cell PD-1, thereby enabling the tumor cell to evade the [140]. Nevertheless, the rational activation and inhibition of autophagy
immune response [125,130,131]. In addition, interferon-γ (IFN-γ) is an by targeting autophagy-related pathways is a promising direction for
important cytokine secreted by various immune cells (e.g., natural killer therapeutic research. Luteolin also induced autophagy, as evidenced by
cells, CD8+, and CD4+ T cells) [132]. IFN-γ has the capacity to increase the accumulation of LC3 II protein, increased LC3 puncta, and enhanced
PD-L1 expression in tumor cells, which would assist them in avoiding autophagic flux that are involved in the death of NCI-H460 lung cancer
immune surveillance and immunological death by suppressing activated cells [141]. This suggests that luteolin may be involved in tumor cell
CD8+ T cells [133]. Similarly, the activation of the JAK/STAT3 signaling death during the early stages of cancer by inducing autophagy.
pathway was also found to increase PD-L1 expression in tumor cells and
promote tumor immune evasion [134]. In patients with KRAS-mutant 6. Pharmacokinetics and safety of luteolin
lung cancer, luteolin and its derivative, apigenin, have been shown to
suppress inducible PD-L1 expression and enhance anti-tumor immunity. Pharmacokinetic qualities are becoming increasingly important in
Luteolin can inhibit the phosphorylation of STAT3 to down-regulate the modern era owing to the ongoing advancements in drug research
IFN-γ-induced PD-L1 expression, block the interaction between PD-1 processes. Moreover, excellent pharmacokinetic properties are indis
and PD-L1 in tumor cells, promote T-cell activity (increased IL-2 pensable evaluation criteria at the drug study stage. The pharmacoki
expression), reduce tumor volume and weight, and exhibit potent anti netic properties of luteolin may be influenced by factors such as gender,
cancer activity in a lung cancer model [14]. This suggests that luteolin age, and genetics [23]. Furthermore, the capacity of the body to absorb
may exert anti-cancer effects by inhibiting the interaction between PD-1 luteolin is impacted by several factors, such as the dosage form, dosage,
and PD-L1 (Fig. 9). delivery method, and the extent of gastrointestinal absorption. Luteolin
can be absorbed through several routes, including oral, intravenous, and
5.7. Autophagy regulation inhalation. A previous study demonstrated that luteolin can be absorbed
rapidly, as its plasma levels (3.04 ± 0.60 μg/mL) peaked at 0.42 h after
Autophagy is a pervasive catabolic process involving the phagocy oral luteolin administration [142]. Notably, rats administered an
tosis of the cell’s own cytoplasmic proteins or organelles into vesicles, intraperitoneal injection of luteolin (60 mg/kg) absorbed it rapidly as
followed by the formation of autophagic lysosomes to degrade the well, with peak levels reached at 0.083 h (71.99 ± 11.04 μg/mL) and a
encapsulated material. The resulting degradation products are subse prolonged half-life (3.2 ± 0.7 h) [143]. Pharmacokinetic parameters in
quently recycled to support metabolic adaptations and maintain energy rat plasma were obtained using HPLC-MS/MS after the oral adminis
homeostasis, ultimately maintaining cellular metabolism and renewal tration of luteolin-enriched Glycyrrhiza uralensis extract to
[135,136]. Autophagy-associated proteins include light chain 3 (LC3), Sprague-Dawley (SD) rats at a dosage of 1 g/kg. The findings revealed
P62 (SQSTM1), and Beclin1. LC3 and P62 are key proteins in autopha that the mean residence time (MRT) 0-t was 20.74 ± 1.91 h; the AUC0-t
gosome formation, while Beclin1 is an important regulator of autopha was 35.01 ± 0.81 h ng/mL; the t1/2 was 31.08 ± 1.17 h; the Cmax was
gosome formation and is involved in autophagy regulation [137,138]. 185 ± 0.12 ng/mL; and the Tmax was 0.87 ± 0.05 h [144]. Luteolin is
Current studies have shown that the activation of autophagy during the primarily absorbed in the colon through passive diffusion, and its ab
early stages of cancer can maintain the stability of the intracellular sorption rate is modulated by the action of metabolic enzymes (cyto
environment by limiting genomic damage and mutation, inhibiting chrome P450 enzymes) in the intestinal wall. Generally, luteolin is
necroinflammation, and selectively removing misfolded proteins, extremely fat-soluble and can be absorbed via the intestinal mucosa,
thereby inhibiting early tumor development [139]. However, when the with higher absorption rates in the jejunum and duodenum compared to
tumor progresses to an advanced stage, autophagy is induced to acti the colon and ileum. For instance, luteolin glycosides are absorbed in the
vate, phagocytose, and decompose macromolecules to supply nutrients intestines following hydrolysis by bacteria or lactose chloride, whereas
for tumor growth in the presence of nutritional deficiencies and hypoxia its aglycones are directly absorbed from the intestine via passive
Fig. 9. Luteolin modulates the immune response. Luteolin modulates the immune response by inhibiting the interaction between PD-1 and PD-L1. IL, Interleukin;
JAK, Janus kinase; STAT3, Signal transducer and activator of transcription 3 (Made with Figdraw).
13
diffusion [23,145]. Research on luteolin metabolism indicates that and detection of components in mixtures through the delicate control of
luteolin is mostly metabolized in the liver through extensive in vivo the interaction between mobile and stationary phases [154]. It has been
metabolism. Its primary metabolic routes are sulfation and glucur used to determine luteolin and resveratrol in rat plasma to study the
onidation, which are performed by sulfonyl transferases and uridine effect of resveratrol on the bioavailability and metabolism of luteolin
diphosphate glucuronosyltransferases, respectively. Furthermore, [155]. Ultraviolet detection is a method of determining the absorbance
methylation is a crucial metabolic route for luteolin [5,23]. Following of a substance in a specific wavelength range for identification, impurity
absorption, luteolin is primarily distributed in the liver, heart, spleen, checking and quantitative determination [153]. Ultra-high-performance
lungs, kidneys, intestines, and other organs and tissues. The distribution liquid chromatography equipped with ultraviolet/photodiode array can
and content order in various tissues is as follows: Heart be used to quantify the detection of luteolin and its derivatives [156].
<Kidneys<Lungs<Spleen<Liver. Additionally, luteolin and its metab Capillary electrophoresis is a liquid-phase separation technique that
olites are predominantly eliminated through the kidneys and biliary uses a capillary tube as a separation channel and is based on differences
tract, and these pathways are primarily influenced by the liver, renal in flow and partitioning behavior between the components of a sample,
function, and medication metabolism [23]. Investigations have indi and has also been used to analyze luteolin [157,158]. It is worth noting
cated that only minimal amounts of luteolin are found in urine (6.6 %) that spectrometry, chromatography, capillary electrophoresis, etc. can
and fecal excretions (31.3 %) following oral administration of luteolin. be used for the detection of luteolin, but these methods have the prob
Additionally, luteolin and its glycosylated forms may undergo a second lems of cumbersome procedures, expensive instruments, high experi
phase of metabolism, generating methylated, sulfated, and/or glucur mental requirements and poor reproducibility. Direct electrochemical
onidated metabolites, which subsequently enter systemic circulation methods, on the other hand, are characterized by high sensitivity, good
and are excreted [5,21]. selectivity, high accuracy, wide measurement range, simple instru
mentation, etc., and have gradually become an indispensable determi
7. Drug delivery system of luteolin nation method [153]. It has shown good results in the analysis and
determination of luteolin in Chrysanthemum tea [159].
The use of luteolin as an effective therapeutic molecule is limited by
its rapid absorption after oral administration, its small absorption and 9. Conclusions and perspectives
rapid excretion from the kidneys combined with its low solubility in
water and its poor degree of systemic absorption. Excessive dosage in Lung cancer is one of the most prevalent malignant tumors and a
creases tend to increase the potential for drug toxicity. New delivery major cause of cancer-related mortality globally. The prognosis for lung
systems and dosage forms have shown significant advantages in cancer is particularly unfavorable; depending on the stage of the disease
improving the fate of luteolin in vivo, including increased bioavailability, at the time of diagnosis, 5-year survival rates vary from 4 % to 17 %.
improved tissue distribution, increased biostability, and reduced Although surgery is an effective treatment option, only 30 % of NSCLC
adverse effects. The Host-guest complexes system allows small molecule cases are diagnosed early, and most patients are already in advanced
components to be encapsulated in a specific way in well-defined porous stages at the time of diagnosis. Conventional therapies, such as chemo-
structures to form a special complex [146]. For example, a novel radiotherapy and novel targeted therapies, provide some hope for the
host-guest complex formed by β-cyclodextrin and luteolin can increase majority of cancer patients; however, there are still safety and efficacy
the anticancer activity and solubility of luteolin by 27-fold and 1, concerns, and multidrug resistance is an issue that needs to be addressed
423-fold, respectively, and is expected to be an anticancer drug for the comprehensive management of cancer. The search for a readily
release system [147]. Phospholipid complexes are more stable com available therapeutic agent with low toxicity and side effects to combat
pounds or complexes formed between drugs and phospholipid molecules lung cancer development and progression is imminent. Luteolin, a
through charge migration. It can change the physicochemical properties flavonoid that can be isolated from vegetables and herbs, exhibits pre
of the parent drug, improve the bioavailability, and the preparation ventive and therapeutic effects on many types of cancer, such as breast
method is simple [148]. The luteolin phospholipid complex was found to cancer, skin cancer, hepatocellular carcinoma, and gastric cancer. By
be 74.14 % loaded, with an average particle size of 147.4 nm, increasing collating previous studies, we conclude that luteolin contain hydroxyl
relative in vivo bioavailability to 535.31 % of pure luteolin [149]. and 2–3 double bonds with anticancer activity in their structure and can
Compared to other drug delivery systems, the most prominent feature of regulate the occurrence and development of lung cancer in many ways,
nano-emulsions is the solubilization of the components [150]. A thus exerting anticancer effects. Firstly, luteolin has strong pro-
low-energy blend of castor oil, kolliphor and polyethylene glycol 200 apoptotic effects and is involved in the regulation of the three major
increases the solubility of luteolin by a factor of approximately 83 [151]. pathways of apoptosis, namely, the mitochondrial, ER, and death re
Luteolin chitosan-encapsulated nano-emulsions increase trans-nasal ceptor pathways, and this mechanism involves the regulation of JNK
mucosal permeation nearly 6-fold, drug half-life 10-fold, and bio activation and modulating oxidative and antioxidant processes; luteolin
distribution of luteolin in brain tissue 4.4-fold after nasal administration can promote apoptosis by targeting MDM4 and PI3K/AKT/MDM2 to
[23]. Another factor contributing to the low bioavailability of luteolin is regulate p53 expression; and other substances, such as HDAC and sirt1,
the glucuronidation of luteolin, and by using inhibitors of the glucur are also involved in the regulation of apoptosis in lung cancer cells by
onidation process, such as resveratrol, the bioavailability of luteolin can luteolin. Secondly, luteolin significantly inhibited tumor cell prolifera
also be significantly improved through the reduction of glucuronidated tion by inhibiting the G1, S, G2, and M phases of the lung cancer cell
metabolites [22]. According to recent studies [152], cycle and regulating the expression of tumor proliferation-associated
nanocarrier-mediated delivery of luteolin via the inhalation route may factors, such as LIMK, PCNA, claudin-2, AR, and TAM RTKs. Luteolin
lead to better drug absorption and is likely to be a novel and very also has a positive effect on suppressing tumor EMT and migration by
effective therapeutic tool for lung cancer. inhibiting the EGFR-PI3K-AKT and integrin β1-FAK/Src signaling path
ways, activating the MEK/ERK signaling pathway, and regulating the
8. Analytical determinations of luteolin and its derivatives expression of migration-associated factors, such as AR, AIM2, and CCL2,
among others. In addition, luteolin plays an important role in mitigating
Currently, the main methods for the determination of luteolin the adverse effects of chemotherapeutic agents and radiosensitization
include high-performance liquid chromatography, ultraviolet spectro through a mechanism involving inhibiting the activation of the Nrf2 and
photometry, capillary electrophoresis and direct electrochemical HGF-MET-Akt signaling pathways. Luteolin has also been shown to
methods [153]. High-performance liquid chromatography is an impor ameliorate cancer complications by attenuating the inflammatory
tant means of analysis, its main function is to achieve rapid separation response by inhibiting the activation of the NF-κB and p38 MAPK
14
signaling pathways. Consequently, it holds potential to be developed as [5] M. Shi, Z. Chen, H. Gong, Z. Peng, Q. Sun, K. Luo, B. Wu, C. Wen, W. Lin,
Luteolin, a flavone ingredient: Anticancer mechanisms, combined medication
a safe and effective substitute treatment for malignant bone pain and
strategy, pharmacokinetics, clinical trials, and pharmaceutical researches.
cachexia. Notably, luteolin also exhibits immunomodulatory effects by Phytother. Res., PTR, 2023.
inhibiting the interaction between PD-1 and PD-L1, and it also partici [6] W.J. Winkelman, Aromatherapy, botanicals, and essential oils in acne, Clin.
pates in tumor cell death during the early stages of cancer by inducing Dermatol. 36 (3) (2018) 299–305.
[7] M.T. Rocchetti, F. Bellanti, M. Zadorozhna, D. Fiocco, D. Mangieri, Multi-faceted
autophagy. In summary, luteolin holds promise to become an anti-lung role of luteolin in cancer metastasis: EMT, angiogenesis, ECM degradation and
cancer therapeutic agent. apoptosis, Int. J. Mol. Sci. 24 (10) (2023).
Based on the current findings, there are still some aspects that [8] L. Wu, Y. Lin, S. Gao, Y. Wang, H. Pan, Z. Wang, M. Pozzolini, F. Yang, H. Zhang,
Y. Yang, L. Xiao, Y. Xu, Luteolin inhibits triple-negative breast cancer by inducing
deserve deeper investigation. Firstly, luteolin demonstrated good anti apoptosis and autophagy through SGK1-FOXO3a-BNIP3 signaling, Front.
cancer effects in the current findings, but the concentration of drugs Pharmacol. 14 (2023) 1200843.
exerting different anticancer mechanisms has not been clearly indicated, [9] A.M. Juszczak, U. Wöelfle, M.Z. Končić, M. Tomczyk, Skin cancer, including
related pathways and therapy and the role of luteolin derivatives as potential
and the mechanism of action of luteolin on different lung cancer sub therapeutics, Med. Res. Rev. 42 (4) (2022) 1423–1462.
types needs to be further investigated. The vast majority of studies have [10] X. Hao, M. Zu, J. Ning, X. Zhou, Y. Gong, X. Han, Q. Meng, D. Li, S. Ding,
been conducted in vitro, with only a few in experimental animals and Antitumor effect of luteolin proven by patient-derived organoids of gastric
cancer, Phytother. Res.: PTR 37 (11) (2023) 5315–5327.
none in humans, making the future clinical application of luteolin a long [11] M. Zhang, R. Wang, J. Tian, M. Song, R. Zhao, K. Liu, F. Zhu, J.H. Shim, Z. Dong,
way off. Moreover, luteolin is typically used at high concentrations M.H. Lee, Targeting LIMK1 with luteolin inhibits the growth of lung cancer in
(1–500 µM) in in vitro studies due to its good anticancer properties. vitro and in vivo, J. Cell. Mol. Med. 25 (12) (2021) 5560–5571.
[12] W. Masraksa, S. Tanasawet, P. Hutamekalin, T. Wongtawatchai, W. Sukketsiri,
However, the current study indicates that luteolin has low bioavail
Luteolin attenuates migration and invasion of lung cancer cells via suppressing
ability, and it is unclear whether luteolin at such a concentration will focal adhesion kinase and non-receptor tyrosine kinase signaling pathway, Nutr.
have good bioavailability in the human body. It’s also crucial to Res. Pract. 14 (2) (2020) 127–133.
remember that luteolin at such high concentrations is likely harmful to [13] S.E. Owumi, S.O. Nwozo, U.O. Arunsi, A.K. Oyelere, O.A. Odunola, Co-
administration of Luteolin mitigated toxicity in rats’ lungs associated with
human health. In order to use luteolin in more effective treatments, doxorubicin treatment, Toxicol. Appl. Pharmacol. 411 (2021) 115380.
more research must be done in the future to determine how to balance [14] Z.B. Jiang, W.J. Wang, C. Xu, Y.J. Xie, X.R. Wang, Y.Z. Zhang, J.M. Huang,
luteolin concentrations, bioavailability, and lowest toxicity doses. On M. Huang, C. Xie, P. Liu, X.X. Fan, Y.P. Ma, P.Y. Yan, L. Liu, X.J. Yao, Q.B. Wu,
E. Lai-Han Leung, Luteolin and its derivative apigenin suppress the inducible PD-
the other hand, it’s important to keep in mind that flavonoids are now L1 expression to improve anti-tumor immunity in KRAS-mutant lung cancer,
frequently referred to as "Pan Assay Interference Compounds." It’s Cancer Lett. 515 (2021) 36–48.
believed that these natural products are most likely ineffective cure-alls, [15] H.J. Cho, K.C. Ahn, J.Y. Choi, S.G. Hwang, W.J. Kim, H.D. Um, J.K. Park, Luteolin
acts as a radiosensitizer in non‑small cell lung cancer cells by enhancing apoptotic
and it’s unclear whether they can be used therapeutically [160,161]. cell death through activation of a p38/ROS/caspase cascade, Int. J. Oncol. 46 (3)
This needs more research. In conclusion, luteolin is a widely available (2015) 1149–1158.
and easy-to-extract modulator of lung cancer that acts via multiple [16] S. Chian, R. Thapa, Z. Chi, X.J. Wang, X. Tang, Luteolin inhibits the Nrf2 signaling
pathway and tumor growth in vivo, Biochem. Biophys. Res. Commun. 447 (4)
mechanisms and can be a potential drug for lung cancer, both in mon (2014) 602–608.
otherapy and combination therapy. [17] L. Huang, M.Y. Kim, J.Y. Cho, Immunopharmacological activities of luteolin in
chronic diseases, Int. J. Mol. Sci. 24 (3) (2023).
[18] H. Singh Tuli, P. Rath, A. Chauhan, K. Sak, D. Aggarwal, R. Choudhary,
CRediT authorship contribution statement U. Sharma, K. Vashishth, S. Sharma, M. Kumar, V. Yadav, T. Singh, M.B. Yerer,
S. Haque, Luteolin, a potent anticancer compound: from chemistry to cellular
Yue Ma: Writing – review & editing, Validation, Supervision. Jin interactions and synergetic perspectives, Cancers 14 (21) (2022).
[19] M.F. Manzoor, N. Ahmad, Z. Ahmed, R. Siddique, X.A. Zeng, A. Rahaman,
Zhang: Writing – original draft, Methodology, Investigation. R. Muhammad Aadil, A. Wahab, Novel extraction techniques and pharmaceutical
activities of luteolin and its derivatives, J. Food Biochem. 43 (9) (2019) e12974.
[20] Y. Hussain, J.H. Cui, H. Khan, M. Aschner, G.E. Batiha, P. Jeandet, Luteolin and
Declaration of Competing Interest cancer metastasis suppression: focus on the role of epithelial to mesenchymal
transition, Med. Oncol. (North., Lond., Engl. ) 38 (6) (2021) 66.
[21] Z. Wang, M. Zeng, Z. Wang, F. Qin, J. Chen, Z. He, Dietary luteolin: a narrative
The authors declare that they have no known competing financial review focusing on its pharmacokinetic properties and effects on glycolipid
interests or personal relationships that could have appeared to influence metabolism, J. Agric. Food Chem. 69 (5) (2021) 1441–1454.
[22] M. Çetinkaya, Y. Baran, Therapeutic potential of luteolin on cancer, Vaccines 11
the work reported in this paper. (3) (2023).
[23] C. Yao, S. Dai, C. Wang, K. Fu, R. Wu, X. Zhao, Y. Yao, Y. Li, Luteolin as a
Data availability potential hepatoprotective drug: molecular mechanisms and treatment strategies,
Biomed. Pharmacother. = Biomed. Pharmacother. 167 (2023) 115464.
[24] A.S. Arampatzis, A. Pampori, E. Droutsa, M. Laskari, P. Karakostas, L. Tsalikis,
Data will be made available on request. P. Barmpalexis, C. Dordas, A.N. Assimopoulou, Occurrence of luteolin in the
greek flora, isolation of luteolin and its action for the treatment of periodontal
Diseases, Molecules 28 (23) (2023).
Acknowledgment [25] S. Ahmed, H. Khan, D. Fratantonio, M.M. Hasan, S. Sharifi, N. Fathi, H. Ullah,
L. Rastrelli, Apoptosis induced by luteolin in breast cancer: mechanistic and
None. therapeutic perspectives, Phytomed.: Int. J. Phytother. Phytopharm. 59 (2019)
152883.
[26] F. Ntalouka, A. Tsirivakou, Luteolin: a promising natural agent in management of
References pain in chronic conditions, Front. Pain. Res. (Lausanne, Switz. ) 4 (2023)
1114428.
[27] N. Muruganathan, A.R. Dhanapal, V. Baskar, P. Muthuramalingam, D. Selvaraj,
[1] M. Salehi, A. Movahedpour, A. Tayarani, Z. Shabaninejad, M.H. Pourhanifeh,
H. Aara, M.Z. Shiek Abdullah, I. Sivanesan, Recent updates on source,
E. Mortezapour, A. Nickdasti, R. Mottaghi, A. Davoodabadi, H. Khan,
biosynthesis, and therapeutic potential of natural flavonoid luteolin: a review,
A. Savardashtaki, H. Mirzaei, Therapeutic potentials of curcumin in the treatment
Metabolites 12 (11) (2022).
of non-small-cell lung carcinoma, Phytother. Res.: PTR 34 (10) (2020)
[28] S. Caporali, A. De Stefano, C. Calabrese, A. Giovannelli, M. Pieri, I. Savini,
2557–2576.
M. Tesauro, S. Bernardini, M. Minieri, A. Terrinoni, Anti-inflammatory and active
[2] Y. Wang, S. Zou, Z. Zhao, P. Liu, C. Ke, S. Xu, New insights into small-cell lung
biological properties of the plant-derived bioactive compounds luteolin and
cancer development and therapy, Cell Biol. Int. 44 (8) (2020) 1564–1576.
luteolin 7-glucoside, Nutrients 14 (6) (2022).
[3] K. Wadowska, I. Bil-Lula, M. Trembecki, Śliwińska-Mossoń, genetic markers in
[29] S. Li, A. Wang, Y. Wu, S. He, W. Shuai, M. Zhao, Y. Zhu, X. Hu, Y. Luo, G. Wang,
lung cancer diagnosis: a review, Int. J. Mol. Sci. 21 (13) (2020).
Targeted therapy for non-small-cell lung cancer: new insights into regulated cell
[4] C.H. Chuang, H.L. Chen, H.M. Chang, Y.C. Tsai, K.L. Wu, I.H. Chen, K.C. Chen, J.
death combined with immunotherapy, Immunol. Rev. (2023).
Y. Lee, Y.C. Chang, C.L. Chen, Y.K. Tu, J.Y. Hung, C.J. Yang, I.W. Chong,
[30] S. Das, N. Shukla, S.S. Singh, S. Kushwaha, R. Shrivastava, Mechanism of
Systematic review and network meta-analysis of anaplastic lymphoma kinase
interaction between autophagy and apoptosis in cancer, Apoptosis: an
(ALK) inhibitors for treatment-naïve ALK-positive lung cancer, Cancers 13 (8)
international journal on programmed, Cell death 26 (9-10) (2021) 512–533.
(2021).
15
[31] Y. Dong, H. Chen, J. Gao, Y. Liu, J. Li, J. Wang, Molecular machinery and [58] H. Zheng, X. Zhu, E. Gong, Y. Lv, Y. Li, X. Cai, Luteolin suppresses lung cancer
interplay of apoptosis and autophagy in coronary heart disease, J. Mol. Cell. progression through targeting the circ_0000190/miR-130a-3p/notch-1 signaling
Cardiol. 136 (2019) 27–41. pathway, J. Chemother. (Florence, Italy) 35 (4) (2023) 330–342.
[32] L. Xiang, Y. Gao, S. Chen, J. Sun, J. Wu, X. Meng, Therapeutic potential of [59] S. Li, L. Wang, Y. Wang, C. Zhang, Z. Hong, Z. Han, The synthetic lethality of
Scutellaria baicalensis Georgi in lung cancer therapy, Phytomedicine: Int. J. targeting cell cycle checkpoints and PARPs in cancer treatment, J. Hematol.
Phytother. Phytopharm. 95 (2022) 153727. Oncol. 15 (1) (2022) 147.
[33] H. Abolfathi, M. Arabi, M. Sheikhpour, A literature review of microRNA and gene [60] D.M. Kopustinskiene, V. Jakstas, A. Savickas, J. Bernatoniene, Flavonoids as
signaling pathways involved in the apoptosis pathway of lung cancer, Respir. Res. anticancer agents, Nutrients 12 (2) (2020).
24 (1) (2023) 55. [61] M.A. Shah, S.M. Abuzar, K. Ilyas, I. Qadees, M. Bilal, R. Yousaf, R.M.T. Kassim,
[34] H. Alizadeh Zeinabad, E. Szegezdi, TRAIL in the treatment of cancer: from soluble A. Rasul, U. Saleem, M.S. Alves, H. Khan, R. Blundell, P. Jeandet, Ginsenosides in
cytokine to nanosystems, Cancers 14 (20) (2022). cancer: targeting cell cycle arrest and apoptosis, Chem. -Biol. Interact. 382 (2023)
[35] S. Nishihara, T. Yamaoka, F. Ishikawa, K. Higuchi, Y. Hasebe, R. Manabe, 110634.
Y. Kishino, S. Kusumoto, K. Ando, Y. Kuroda, T. Ohmori, H. Sagara, H. Yoshida, [62] Y. Sun, Y. Liu, X. Ma, H. Hu, The influence of cell cycle regulation on
J. Tsurutani, Mechanisms of EGFR-TKI-induced apoptosis and strategies targeting chemotherapy, Int. J. Mol. Sci. 22 (13) (2021).
apoptosis in EGFR-mutated non-small cell lung cancer, Genes 13 (12) (2022). [63] A.K. Witkiewicz, V. Kumarasamy, I. Sanidas, E.S. Knudsen, Cancer cell cycle
[36] H. Xiao, Q. Xue, Q. Zhang, C. Li, X. Liu, J. Liu, H. Li, J. Yang, How ginsenosides dystopia: heterogeneity, plasticity, and therapy, Trends Cancer 8 (9) (2022)
trigger apoptosis in human lung adenocarcinoma cells, Am. J. Chin. Med. 47 (8) 711–725.
(2019) 1737–1754. [64] H.K. Matthews, C. Bertoli, R.A.M. de Bruin, Cell cycle control in cancer, Nat. Rev.
[37] J.L. Morris, G. Gillet, J. Prudent, N. Popgeorgiev, Bcl-2 family of proteins in the Mol. Cell Biol. 23 (1) (2022) 74–88.
control of mitochondrial calcium signalling: an old chap with new roles, Int. J. [65] J.M. Suski, M. Braun, V. Strmiska, P. Sicinski, Targeting cell-cycle machinery in
Mol. Sci. 22 (7) (2021). cancer, Cancer Cell 39 (6) (2021) 759–778.
[38] S. Barillé-Nion, S. Lohard, P.P. Juin, Targeting of BCL-2 family members during [66] J. Liu, Y. Peng, W. Wei, Cell cycle on the crossroad of tumorigenesis and cancer
anticancer treatment: a necessary compromise between individual cell and therapy, Trends Cell Biol. 32 (1) (2022) 30–44.
ecosystemic responses? Biomolecules 10 (8) (2020). [67] T. Zou, Z. Lin, The involvement of ubiquitination machinery in cell cycle
[39] J.M. Pemberton, J.P. Pogmore, D.W. Andrews, Neuronal cell life, death, and regulation and cancer progression, Int. J. Mol. Sci. 22 (11) (2021).
axonal degeneration as regulated by the BCL-2 family proteins, Cell death Differ. [68] Y. Zhao, G. Yang, D. Ren, X. Zhang, Q. Yin, X. Sun, Luteolin suppresses growth
28 (1) (2021) 108–122. and migration of human lung cancer cells, Mol. Biol. Rep. 38 (2) (2011)
[40] J. Liu, M. Hong, Y. Li, D. Chen, Y. Wu, Y. Hu, Programmed cell death tunes tumor 1115–1119.
immunity, Front. Immunol. 13 (2022) 847345. [69] X. Cai, T. Ye, C. Liu, W. Lu, M. Lu, J. Zhang, M. Wang, P. Cao, Luteolin induced G2
[41] K. Mortezaee, E. Salehi, H. Mirtavoos-Mahyari, E. Motevaseli, M. Najafi, phase cell cycle arrest and apoptosis on non-small cell lung cancer cells, Toxicol.
B. Farhood, R.J. Rosengren, A. Sahebkar, Mechanisms of apoptosis modulation by Vitr.: Int. J. Publ. Assoc. BIBRA 25 (7) (2011) 1385–1391.
curcumin: implications for cancer therapy, J. Cell. Physiol. 234 (8) (2019) [70] H.W. Leung, C.H. Wu, C.H. Lin, H.Z. Lee, Luteolin induced DNA damage leading
12537–12550. to human lung squamous carcinoma CH27 cell apoptosis, Eur. J. Pharmacol. 508
[42] Q. Chen, S. Liu, J. Chen, Q. Zhang, S. Lin, Z. Chen, J. Jiang, Luteolin induces (1-3) (2005) 77–83.
mitochondria-dependent apoptosis in human lung adenocarcinoma cell, Nat. [71] J. Zhao, S. Guo, S.J. Schrodi, D. He, Absent in melanoma 2 (AIM2) in rheumatoid
Prod. Commun. 7 (1) (2012) 29–32. arthritis: novel molecular insights and implications, Cell. Mol. Biol. Lett. 27 (1)
[43] H.Z. Lee, W.H. Yang, B.Y. Bao, P.L. Lo, Proteomic analysis reveals ATP-dependent (2022) 108.
steps and chaperones involvement in luteolin-induced lung cancer CH27 cell [72] Q. Yu, M. Zhang, Q. Ying, X. Xie, S. Yue, B. Tong, Q. Wei, Z. Bai, L. Ma, Decrease
apoptosis, Eur. J. Pharmacol. 642 (1-3) (2010) 19–27. of AIM2 mediated by luteolin contributes to non-small cell lung cancer treatment,
[44] J. Yan, Q. Wang, X. Zheng, H. Sun, Y. Zhou, D. Li, Y. Lin, X. Wang, Luteolin Cell death Dis. 10 (3) (2019) 218.
enhances TNF-related apoptosis-inducing ligand’s anticancer activity in a lung [73] E. Villalonga, C. Mosrin, T. Normand, C. Girardin, A. Serrano, B. Žunar,
cancer xenograft mouse model, Biochem. Biophys. Res. Commun. 417 (2) (2012) M. Doudeau, F. Godin, H. Bénédetti, B. Vallée, LIM Kinases, LIMK1 and LIMK2,
842–846. are crucial node actors of the cell fate: molecular to pathological features, Cells 12
[45] B. Wu, J. Xiong, Y. Zhou, Y. Wu, Y. Song, N. Wang, L. Chen, J. Zhang, Luteolin (5) (2023).
enhances TRAIL sensitivity in non-small cell lung cancer cells through increasing [74] E.R. Kasala, L.N. Bodduluru, C.C. Barua, R. Gogoi, Antioxidant and antitumor
DR5 expression and Drp1-mediated mitochondrial fission, Arch. Biochem. efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental
Biophys. 692 (2020) 108539. lung carcinogenesis, Biomed. Pharmacother. = Biomedecine Pharmacother. 82
[46] W. Ju, X. Wang, H. Shi, W. Chen, S.A. Belinsky, Y. Lin, A critical role of luteolin- (2016) 568–577.
induced reactive oxygen species in blockage of tumor necrosis factor-activated [75] M. Cardano, C. Tribioli, E. Prosperi, Targeting proliferating cell nuclear antigen
nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells, (PCNA) as an effective strategy to inhibit tumor cell proliferation, Curr. Cancer
Mol. Pharmacol. 71 (5) (2007) 1381–1388. Drug Targets 20 (4) (2020) 240–252.
[47] L. Bai, W. Chen, X. Wang, W. Ju, S. Xu, Y. Lin, Attenuating Smac mimetic [76] S. Zhang, T. Zhou, Z. Wang, F. Yi, C. Li, W. Guo, H. Xu, H. Cui, X. Dong, J. Liu,
compound 3-induced NF-kappaB activation by luteolin leads to synergistic X. Song, L. Cao, Post-translational modifications of PCNA in control of DNA
cytotoxicity in cancer cells, J. Cell. Biochem. 108 (5) (2009) 1125–1131. synthesis and DNA damage tolerance-the implications in carcinogenesis, Int. J.
[48] L. Bai, X. Xu, Q. Wang, S. Xu, W. Ju, X. Wang, W. Chen, W. He, H. Tang, Y. Lin, Biol. Sci. 17 (14) (2021) 4047–4059.
A superoxide-mediated mitogen-activated protein kinase phosphatase-1 [77] S. Venugopal, S. Anwer, K. Szászi, Claudin-2: roles beyond permeability
degradation and c-Jun NH(2)-terminal kinase activation pathway for luteolin- functions, Int. J. Mol. Sci. 20 (22) (2019).
induced lung cancer cytotoxicity, Mol. Pharmacol. 81 (4) (2012) 549–555. [78] H. Sonoki, A. Tanimae, S. Endo, T. Matsunaga, T. Furuta, K. Ichihara, A. Ikari,
[49] H.W. Leung, C.L. Kuo, W.H. Yang, C.H. Lin, H.Z. Lee, Antioxidant enzymes Kaempherol and luteolin decrease claudin-2 expression mediated by inhibition of
activity involvement in luteolin-induced human lung squamous carcinoma CH27 STAT3 in lung adenocarcinoma A549 cells, Nutrients 9 (6) (2017).
cell apoptosis, Eur. J. Pharmacol. 534 (1-3) (2006) 12–18. [79] A. Jacob, R. Raj, D.B. Allison, Z.W. Myint, Androgen receptor signaling in
[50] H. Wang, M. Guo, H. Wei, Y. Chen, Targeting p53 pathways: mechanisms, prostate cancer and therapeutic strategies, Cancers 13 (21) (2021).
structures, and advances in therapy, Signal Transduct. Target. Ther. 8 (1) (2023) [80] X. Li, Y. Tang, P. Liang, M. Sun, T. Li, Z. Shen, S. Sha, Luteolin inhibits A549 cells
92. proliferation and migration by down-regulating androgen receptors, Eur. J. Med.
[51] K. McElhinney, M. Irnaten, C. O’Brien, p53 and Myofibroblast Apoptosis in Organ Res. 28 (1) (2023) 353.
Fibrosis, Int. J. Mol. Sci. 24 (7) (2023). [81] D. DeRyckere, J.M. Huelse, H.S. Earp, D.K. Graham, TAM family kinases as
[52] Z.Q. Jiang, M.H. Li, Y.M. Qin, H.Y. Jiang, X. Zhang, M.H. Wu, Luteolin inhibits therapeutic targets at the interface of cancer and immunity, Nat. Rev. Clin. Oncol.
tumorigenesis and induces apoptosis of non-small cell lung cancer cells via 20 (11) (2023) 755–779.
regulation of MicroRNA-34a-5p, Int. J. Mol. Sci. 19 (2) (2018). [82] Y.J. Lee, T. Lim, M.S. Han, S.H. Lee, S.H. Baek, H.Y. Nan, C. Lee, Anticancer effect
[53] B. Ye, P. Chen, C. Lin, C. Zhang, L. Li, Study on the material basis and action of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but
mechanisms of Sophora davidii (Franch.) skeels flower extract in the treatment of not interleukin-8, in non-small cell lung cancer cells, Oncol. Rep. 37 (2) (2017)
non-small cell lung cancer, J. Ethnopharmacol. 317 (2023) 116815. 1219–1226.
[54] Y. Sun, J.H. Hong, Z. Ning, D. Pan, X. Fu, X. Lu, J. Tan, Therapeutic potential of [83] S.U. Khan, K. Fatima, F. Malik, H. Kalkavan, A. Wani, Cancer metastasis:
tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment, Front. Molecular mechanisms and clinical perspectives, Pharmacol. Ther. 250 (2023)
Pharmacol. 13 (2022) 932914. 108522.
[55] S. Attoub, A.H. Hassan, B. Vanhoecke, R. Iratni, T. Takahashi, A.M. Gaben, [84] S. Xie, Z. Wu, Y. Qi, B. Wu, X. Zhu, The metastasizing mechanisms of lung cancer:
M. Bracke, S. Awad, A. John, H.A. Kamalboor, M.A. Al Sultan, K. Arafat, Recent advances and therapeutic challenges, Biomed. Pharmacother. =
C. Gespach, G. Petroianu, Inhibition of cell survival, invasion, tumor growth and Biomedecine Pharmacother. 138 (2021) 111450.
histone deacetylase activity by the dietary flavonoid luteolin in human [85] M. Park, D. Kim, S. Ko, A. Kim, K. Mo, H. Yoon, Breast cancer metastasis:
epithelioid cancer cells, Eur. J. Pharmacol. 651 (1-3) (2011) 18–25. mechanisms and therapeutic implications, Int. J. Mol. Sci. 23 (12) (2022).
[56] F. Deniz, G. Eren, I.E. Orhan, Flavonoids as sirtuin modulators, Curr. Top. Med. [86] I. Martinez-Espinosa, J.A. Serrato, B. Ortiz-Quintero, The Role of Exosome-
Chem. 22 (9) (2022) 790–805. Derived microRNA on Lung Cancer Metastasis Progression, Biomolecules 13 (11)
[57] L. Ma, H. Peng, K. Li, R. Zhao, L. Li, Y. Yu, X. Wang, Z. Han, Luteolin exerts an (2023).
anticancer effect on NCI-H460 human non-small cell lung cancer cells through the [87] J. Ko, M.M. Winslow, J. Sage, Mechanisms of small cell lung cancer metastasis,
induction of Sirt1-mediated apoptosis, Mol. Med. Rep. 12 (3) (2015) 4196–4202. EMBO Mol. Med. 13 (1) (2021) e13122.
16
[88] Y. Huang, W. Hong, X. Wei, The molecular mechanisms and therapeutic strategies [115] D.C. Hughes, C.A. Goodman, L.M. Baehr, P. Gregorevic, S.C. Bodine, A critical
of EMT in tumor progression and metastasis, J. Hematol. Oncol. 15 (1) (2022) discussion on the relationship between E3 ubiquitin ligases, protein degradation,
129. and skeletal muscle wasting: it’s not that simple, American journal of physiology,
[89] L. Avila-Carrasco, P. Majano, J.A. Sánchez-Toméro, R. Selgas, M. López-Cabrera, Cell Physiol. 325 (6) (2023).
A. Aguilera, G. González Mateo, Natural Plants Compounds as Modulators of [116] B. Gellhaus, K.O. Böker, A.F. Schilling, D. Saul, Therapeutic Consequences of
Epithelial-to-Mesenchymal Transition, Front. Pharmacol. 10 (2019) 715. Targeting the IGF-1/PI3K/AKT/FOXO3 Axis in Sarcopenia: A Narrative Review,
[90] M. Sisto, D. Ribatti, S. Lisi, SMADS-Mediate Molecular Mechanisms in Sjögren’s Cells 12 (24) (2023).
Syndrome, Int. J. Mol. Sci. 22 (6) (2021). [117] I. Yoshihara, Y. Kondo, K. Okamoto, H. Tanaka, Sepsis-associated muscle wasting:
[91] D.H.L. Leung, B.W.S. Phon, M. Sivalingam, A.K. Radhakrishnan, M.N. a comprehensive review from bench to bedside, Int. J. Mol. Sci. 24 (5) (2023).
A. Kamarudin, Regulation of EMT markers, extracellular matrix, and associated [118] F. Yarmohammadi, A.W. Hayes, G. Karimi, Protective effects of curcumin on
signalling pathways by long non-coding RNAs in glioblastoma mesenchymal chemical and drug-induced cardiotoxicity: a review, Naunyn-Schmiede ’S. Arch.
transition: a scoping review, Biology 12 (6) (2023). Pharmacol. 394 (7) (2021) 1341–1353.
[92] A. Barzegar Behrooz, Z. Talaie, F. Jusheghani, M.J. Łos, T. Klonisch, S. Ghavami, [119] T. Chen, B. Li, Y. Xu, S. Meng, Y. Wang, Y. Jiang, Luteolin reduces cancer‑induced
Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in skeletal and cardiac muscle atrophy in a Lewis lung cancer mouse model, Oncol.
Glioblastoma, Int. J. Mol. Sci. 23 (3) (2022). Rep. 40(2 (2018) 1129–1137.
[93] K.C. Chen, C.Y. Chen, C.R. Lin, T.Y. Yang, T.H. Chen, L.C. Wu, C.C. Wu, Luteolin [120] Y.S. Zhou, Y. Cui, J.X. Zheng, Y.Q. Quan, S.X. Wu, H. Xu, Y. Han, Luteolin relieves
attenuates TGF-β1-induced epithelial-mesenchymal transition of lung cancer cells lung cancer-induced bone pain by inhibiting NLRP3 inflammasomes and glial
by interfering in the PI3K/Akt-NF-κB-Snail pathway, Life Sci. 93 (24) (2013) activation in the spinal dorsal horn in mice, Phytomedicine: Int. J. Phytother.
924–933. Phytopharm. 96 (2022) 153910.
[94] Z. Hong, X. Cao, N. Li, Y. Zhang, L. Lan, Y. Zhou, X. Pan, L. Shen, Z. Yin, L. Luo, [121] M.R. Conroy, C. Dennehy, P.M. Forde, Neoadjuvant immune checkpoint inhibitor
Luteolin is effective in the non-small cell lung cancer model with L858R/T790M therapy in resectable non-small cell lung cancer, Lung Cancer 183 (2023) 107314.
EGF receptor mutation and erlotinib resistance, Br. J. Pharmacol. 171 (11) (2014) [122] S. Yang, Z. Zhang, Q. Wang, Emerging therapies for small cell lung cancer,
2842–2853. J. Hematol. Oncol. 12 (1) (2019) 47.
[95] H.W. Lin, T.J. Shen, N.C. Yang, M. Wang, W.C. Hsieh, C.J. Chuang, C.Y. Lai, Y. [123] H. Zhang, Z. Dai, W. Wu, Z. Wang, N. Zhang, L. Zhang, W.J. Zeng, Z. Liu,
Y. Chang, Luteolin reduces aqueous extract PM2.5-induced metastatic activity in Q. Cheng, Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in
H460 lung cancer cells, Int. J. Med. Sci. 19 (10) (2022) 1502–1509. cancer, J. Exp. Clin. Cancer Res.: CR 40 (1) (2021) 184.
[96] J. Ruan, L. Zhang, L. Yan, Y. Liu, Z. Yue, L. Chen, A.Y. Wang, W. Chen, S. Zheng, [124] Y. Wu, W. Chen, Z.P. Xu, W. Gu, PD-L1 Distribution and Perspective for Cancer
S. Wang, Y. Lu, Inhibition of hypoxia-induced epithelial mesenchymal transition Immunotherapy-Blockade, Knockdown, or Inhibition, Front. Immunol. 10 (2019)
by luteolin in non-small cell lung cancer cells, Mol. Med. Rep. 6 (1) (2012) 2022.
232–238. [125] M. Yi, X. Zheng, M. Niu, S. Zhu, H. Ge, K. Wu, Combination strategies with PD-1/
[97] G. Meng, K. Chai, X. Li, Y. Zhu, W. Huang, Luteolin exerts pro-apoptotic effect and PD-L1 blockade: current advances and future directions, Mol. Cancer 21 (1)
anti-migration effects on A549 lung adenocarcinoma cells through the activation (2022) 28.
of MEK/ERK signaling pathway, Chem. -Biol. Interact. 257 (2016) 26–34. [126] Q. Tang, Y. Chen, X. Li, S. Long, Y. Shi, Y. Yu, W. Wu, L. Han, S. Wang, The role of
[98] H.J. Choi, H.J. Choi, T.W. Chung, K.T. Ha, Luteolin inhibits recruitment of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers,
monocytes and migration of Lewis lung carcinoma cells by suppressing Front. Immunol. 13 (2022) 964442.
chemokine (C-C motif) ligand 2 expression in tumor-associated macrophage, [127] N. Patsoukis, Q. Wang, L. Strauss, V.A. Boussiotis, Revisiting the PD-1 pathway,
Biochem. Biophys. Res. Commun. 470 (1) (2016) 101–106. Sci. Adv. 6 (38) (2020).
[99] J. Wu, Z. Lin, Non-small cell lung cancer targeted therapy: drugs and mechanisms [128] Y. Han, D. Liu, L. Li, PD-1/PD-L1 pathway: current researches in cancer, Am. J.
of drug resistance, Int. J. Mol. Sci. 23 (23) (2022). Cancer Res. 10 (3) (2020) 727–742.
[100] A. Lahiri, A. Maji, P.D. Potdar, N. Singh, P. Parikh, B. Bisht, A. Mukherjee, M. [129] S. De Almeida, M. Regimbeau, G. Jego, C. Garrido, F. Girodon, F. Hermetet, Heat
K. Paul, Lung cancer immunotherapy: progress, pitfalls, and promises, Mol. Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in
Cancer 22 (1) (2023) 40. Myeloproliferative Neoplasms, Cancers 12 (9) (2020).
[101] S.K. Vinod, E. Hau, Radiotherapy treatment for lung cancer: Current status and [130] H. Yamaguchi, J.M. Hsu, W.H. Yang, M.C. Hung, Mechanisms regulating PD-L1
future directions, Respirol. (Carlton, Vic. ) 25 (Suppl 2) (2020) 61–71. expression in cancers and associated opportunities for novel small-molecule
[102] C. Jie, R. Li, Y. Cheng, Z. Wang, Q. Wu, C. Xie, Prospects and feasibility of therapeutics, Nat. Rev. Clin. Oncol. 19 (5) (2022) 287–305.
synergistic therapy with radiotherapy, immunotherapy, and DNA [131] E. Dantoing, N. Piton, M. Salaün, L. Thiberville, F. Guisier, Anti-PD1/PD-L1
methyltransferase inhibitors in non-small cell lung cancer, Front. Immunol. 14 immunotherapy for non-small cell lung cancer with actionable oncogenic driver
(2023) 1122352. mutations, Int. J. Mol. Sci. 22 (12) (2021).
[103] J. Zhao, X. Lin, D. Meng, L. Zeng, R. Zhuang, S. Huang, W. Lv, J. Hu, Nrf2 [132] D. Jorgovanovic, M. Song, L. Wang, Y. Zhang, Roles of IFN-γ in tumor progression
mediates metabolic reprogramming in non-small cell lung cancer, Front. Oncol. and regression: a review, Biomark. Res. 8 (2020) 49.
10 (2020) 578315. [133] H. Cai, Y. Zhang, J. Wang, J. Gu, Defects in macrophage reprogramming in cancer
[104] S. Ghareghomi, F. Moosavi-Movahedi, L. Saso, M. Habibi-Rezaei, A. Khatibi, therapy: the negative impact of PD-L1/PD-1, Front. Immunol. 12 (2021) 690869.
J. Hong, A.A. Moosavi-Movahedi, Modulation of Nrf2/HO-1 by natural [134] F. Zhu, K.B. Wang, L. Rui, STAT3 activation and oncogenesis in lymphoma,
compounds in lung cancer, Antioxidants 12 (3) (2023). Cancers 12 (1) (2019).
[105] X. Tang, H. Wang, L. Fan, X. Wu, A. Xin, H. Ren, X.J. Wang, Luteolin inhibits Nrf2 [135] M. Shahverdi, K. Hajiasgharzadeh, A.D. Sorkhabi, M. Jafarlou, M. Shojaee,
leading to negative regulation of the Nrf2/ARE pathway and sensitization of N. Jalili Tabrizi, N. Alizadeh, M. Santarpia, O. Brunetti, H. Safarpour,
human lung carcinoma A549 cells to therapeutic drugs, Free Radic. Biol. Med. 50 N. Silvestris, B. Baradaran, The regulatory role of autophagy-related miRNAs in
(11) (2011) 1599–1609. lung cancer drug resistance, Biomed. Pharmacother. = Biomedecine
[106] G. Huang, X. Liu, T. Jiang, Y. Cao, M. Sang, X. Song, B. Zhou, H. Qu, H. Cai, Pharmacother. 148 (2022) 112735.
D. Xing, Y. Mao, G. Lin, X. Liu, X. Zheng, Luteolin overcomes acquired resistance [136] W. Guo, K. Du, S. Luo, D. Hu, Recent advances of autophagy in non-small cell lung
to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt cancer: from basic mechanisms to clinical application, Front. Oncol. 12 (2022)
pathway, Am. J. Cancer Res. 13 (9) (2023) 4145–4162. 861959.
[107] C. Calcabrini, F. Maffei, E. Turrini, C. Fimognari, Sulforaphane potentiates [137] X.L. Su, J.W. Wang, H. Che, C.F. Wang, H. Jiang, X. Lei, W. Zhao, H.X. Kuang, Q.
anticancer effects of doxorubicin and cisplatin and mitigates their toxic effects, H. Wang, Clinical application and mechanism of traditional Chinese medicine in
Front. Pharmacol. 11 (2020) 567. treatment of lung cancer, Chin. Med. J. 133 (24) (2020) 2987–2997.
[108] J. Ni, L. Zhang, Cancer cachexia: definition, staging, and emerging treatments, [138] J. Debnath, N. Gammoh, K.M. Ryan, Autophagy and autophagy-related pathways
Cancer Manag. Res. 12 (2020) 5597–5605. in cancer, Nat. Rev. Mol. Cell Biol. 24 (8) (2023) 560–575.
[109] J.M. Argilés, F.J. López-Soriano, B. Stemmler, S. Busquets, Cancer-associated [139] D.R. Miller, A. Thorburn, Autophagy and organelle homeostasis in cancer, Dev.
cachexia - understanding the tumour macroenvironment and microenvironment Cell 56 (7) (2021) 906–918.
to improve management, Nat. Rev. Clin. Oncol. 20 (4) (2023) 250–264. [140] I. Ganzleben, M.F. Neurath, C. Becker, Autophagy in cancer therapy-molecular
[110] H. Baazim, L. Antonio-Herrera, A. Bergthaler, The interplay of immunology and mechanisms and current clinical advances, Cancers 13 (21) (2021).
cachexia in infection and cancer, Nat. Rev. Immunol. 22 (5) (2022) 309–321. [141] S.H. Park, H.S. Park, J.H. Lee, G.Y. Chi, G.Y. Kim, S.K. Moon, Y.C. Chang, J.
[111] T. Setiawan, I.N. Sari, Y.T. Wijaya, N.M. Julianto, J.A. Muhammad, H. Lee, J. W. Hyun, W.J. Kim, Y.H. Choi, Induction of endoplasmic reticulum stress-
H. Chae, H.Y. Kwon, Cancer cachexia: molecular mechanisms and treatment mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung
strategies, J. Hematol. Oncol. 16 (1) (2023) 54. carcinoma cells, Food Chem. Toxicol.: Int. J. Publ. Br. Ind. Biol. Res. Assoc. 56
[112] S. Peixoto da Silva, J.M.O. Santos, E.S.M.P. Costa, R.M. Gil da Costa, R. Medeiros, (2013) 100–109.
Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and [142] X. Dong, W. Lan, X. Yin, C. Yang, W. Wang, J. Ni, Simultaneous determination
asthenia, J. Cachex-.-., Sarcopenia Muscle 11 (3) (2020) 619–635. and pharmacokinetic study of quercetin, luteolin, and apigenin in rat plasma after
[113] M. Ferrer, T.G. Anthony, J.S. Ayres, G. Biffi, J.C. Brown, B.J. Caan, E.M. Cespedes oral administration of matricaria chamomilla L. extract by HPLC-UV, evidence-
Feliciano, A.P. Coll, R.F. Dunne, M.D. Goncalves, J. Grethlein, S.B. Heymsfield, based complementary and alternative medicine, eCAM 2017 (2017) 8370584.
S. Hui, M. Jamal-Hanjani, J.M. Lam, D.Y. Lewis, D. McCandlish, K.M. Mustian, [143] F. Shi, H. Pan, Y. Lu, L. Ding, An HPLC-MS/MS method for the simultaneous
S. O’Rahilly, N. Perrimon, E.P. White, T. Janowitz, Cachexia: a systemic determination of luteolin and its major metabolites in rat plasma and its
consequence of progressive, unresolved disease, Cell 186 (9) (2023) 1824–1845. application to a pharmacokinetic study, J. Sep. Sci. 41 (20) (2018) 3830–3839.
[114] S. Haberecht-Müller, E. Krüger, J. Fielitz, Out of control: the role of the ubiquitin [144] H. Liu, G. Chang, W. Wang, Z. Ji, J. Cui, Y. Peng, Pharmacokinetics, prostate
proteasome system in skeletal muscle during inflammation, Biomolecules 11 (9) distribution and metabolic characteristics of four representative flavones after
(2021).
17
oral administration of the aerial part of glycyrrhiza uralensis in rats, Molecules 27 [154] F. Hameedat, S. Hawamdeh, S. Alnabulsi, A. Zayed, High Performance liquid
(10) (2022). chromatography (HPLC) with fluorescence detection for quantification of steroids
[145] X.Y. Lu, D.L. Sun, Z.J. Chen, T. Chen, L.P. Li, Z.H. Xu, H.D. Jiang, S. Zeng, Relative in clinical, pharmaceutical, and environmental samples: a review, Molecules 27
contribution of small and large intestine to deglycosylation and absorption of (6) (2022).
flavonoids from Chrysanthemun morifolium extract, J. Agric. Food Chem. 58 (19) [155] W. Wu, K. Li, C. Zhao, X. Ran, Y. Zhang, T. Zhang, A rapid HPLC-MS/MS method
(2010) 10661–10667. for the simultaneous determination of luteolin, resveratrol and their metabolites
[146] W. Jogadi, Y.R. Zheng, Supramolecular platinum complexes for cancer therapy, in rat plasma and its application to pharmacokinetic interaction studies,
Curr. Opin. Chem. Biol. 73 (2023) 102276. J. Chromatogr. B, Anal. Technol. Biomed. life Sci. 1191 (2022) 123118.
[147] P. Zhu, L. Chen, Y. Zhao, C. Gao, J. Yang, X. Liao, D. Liu, B. Yang, A novel host- [156] M.S. Che Zain, M.F. Osman, S.Y. Lee, K. Shaari, UHPLC-UV/PDA Method
guest complex based on biotin functionalized polyamine-β-cyclodextrin for tumor Validation for Simultaneous Quantification of Luteolin and Apigenin Derivatives
targeted delivery of luteolin, J. Mol. Struct. 1237 (2021). from Elaeis guineensis Leaf Extracts: An Application for Antioxidant Herbal
[148] H. Wang, J. Luo, Y. Zhang, D. He, R. Jiang, X. Xie, Q. Yang, K. Li, J. Xie, J. Zhang, Preparation, Mol. (Basel, Switz. ) 26 (4) (2021).
Phospholipid/hydroxypropyl-β-cyclodextrin supramolecular complexes are [157] W. Li, X. Cui, Z. Chen, Screening of lactate dehydrogenase inhibitor from
promising candidates for efficient oral delivery of curcuminoids, Int. J. Pharm. bioactive compounds in natural products by electrophoretically mediated
582 (2020) 119301. microanalysis, J. Chromatogr. A 1656 (2021) 462554.
[149] J. Khan, S. Saraf, S. Saraf, Preparation and evaluation of luteolin-phospholipid [158] B. Seyfinejad, A. Jouyban, Capillary electrophoresis-mass spectrometry in
complex as an effective drug delivery tool against GalN/LPS induced liver pharmaceutical and biomedical analyses, J. Pharm. Biomed. Anal. 221 (2022)
damage, Pharm. Dev. Technol. 21 (4) (2016). 115059.
[150] M.K. Sah, B. Gautam, K.P. Pokhrel, L. Ghani, A. Bhattarai, Quantification of the [159] X. Chen, J. Li, J. Li, L. Zhang, P. Zhao, C. Wang, J. Fei, Y. Xie, Determination of
quercetin nanoemulsion technique using various parameters, Molecules 28 (6) luteolin in Chrysanthemum tea with a ultra-sensitive electrochemical sensor
(2023). based on MoO(3)/poly(3,4-ethylene dioxythiophene)/gama-cyclodextrin metal-
[151] M.J. Ansari, A. Alshetaili, I.A. Aldayel, F.M. Alablan, B. Alsulays, S. Alshahrani, organic framework composites, Food Chem. 397 (2022) 133723.
A. Alalaiwe, M.N. Ansari, N. Ur Rehman, F. Shakeel, Formulation, [160] J. Bisson, J.B. McAlpine, J.B. Friesen, S.N. Chen, J. Graham, G.F. Pauli, Can
characterization, in vitro and in vivo evaluations of self-nanoemulsifying drug invalid bioactives undermine natural product-based drug discovery? J. Med.
delivery system of luteolin, J. Taibah Univ. Sci. 14 (1) (2020) 1386–1401. Chem. 59 (5) (2016) 1671–1690.
[152] N. Ara, A. Hafeez, Nanocarrier-mediated drug delivery via inhalational route for [161] S.J. Capuzzi, E.N. Muratov, A. Tropsha, Phantom PAINS: problems with the utility
lung cancer therapy: a systematic and updated review, AAPS PharmSciTech 25 of alerts for pan-assay interference compounds, J. Chem. Inf. Model. 57 (3) (2017)
(3) (2024) 47. 417–427.
[153] A.Y. Tesio, S.N. Robledo, Analytical determinations of luteolin, BioFactors (Oxf.,
Engl. ) 47 (2) (2021) 141–164.
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Biomedicine & Pharmacotherapy 176 (2024) 116909

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Luteolin as a potential therapeutic candidate for lung cancer: Emerging

5. Mechanisms of luteolin against lung cancer

5.1. Pro-apoptotic effects

Apoptosis is a genetically encoded programmed cell death [29].

aging and longevity, diabetes mellitus, and inflammation, with sirt1

5.2. Inhibition of cell proliferation

The distinguishing biological characteristic of tumor cells is that they

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