Drug repurposing: promising source of innovative cancer

therapy
Rupali Ghosh1, Sarla1, Dr. Saima Wajid* (swajid@jamiahamdard.ac.in)

1. Department of Biotechnology, School of Chemical and Life Science, Jamia

Hamdard, New Delhi-110062, India.

2. Department of Biotechnology, School of Chemical and Life Science, Jamia

Hamdard, New Delhi-110062, India.

Address for Correspondence:

Dr. Saima Wajid

Department of BioTechnology

Jamia Hamdard

Hamdard Nagar

New Delhi – 110062

Phone: 9899823898

Email: swajid@jamiahamdard.ac.in

Abstract: Cancer is the major cause of death worldwide, with 2.25 million cancer
cases. Breast cancer is the most prevalent cancer in women worldwide with a high
mortality rate. Inhibition of MCT4 combined with metformin/NF-K Bi can be used in
the treatment of BC. Pancreatic cancer is one of the deadliest cancers worldwide as
the patients rarely show symptoms of an advanced stage of cancer. PCA cases were
detected in 85% in the III and IV stage, making it difficult to treat. According to
ICMR, lung cancer is the most persistent cancer responsible for 9.3% of cancer
deaths. Re-purposing non-oncology drugs is a better therapeutic option for cancer
treatment. The process of developing conventional drugs is a multi-step process,
money, and time-consuming. To overcome these disadvantages, a strategy of re-
purposing came into the picture. Anti-hypertensive, NSAIDs, anti-inflammatory, anti-
diabetic, anti-retro viral, anti-and microbial, and anti-malarial are the different
categories of repurposed drugs used in the treatment of cancer. This review focuses on
the mechanism of action and biological targets of repurposing which show anti-
cancerous activity. The immunomodulatory role of repurposed drugs can explore their
potential application in cancer treatment in the future.

Keywords: Repurposed drugs, metformin, ICMR, BC, PCA, biological targets.

Introduction:
Cancer is defined as the uncontrolled division of cells due to mutations in DNA
having the potential to spread to different parts of the body. Cancerous cells lead to
metastasis of the lymphatic system. During cancer progression, tumors become
heterogeneous, characterized by different molecular features and wide responses to
treatment. The major challenges in cancer treatment are the survival rate,
complications, poor prognosis, and recurrence [1]. More than 200 different types of
cancer are identified which are named according to the tissue where it persists i.e.,
breast, lung, cervical, colon, and pancreatic cancer. Breast and lung cancer are the
most invasive type of cancer contributing 12.5% and 12.2% of the total cancer cases
reported. According to the Global Cancer Data 2022, 19.3 million cancer cases and 10
million cancer deaths worldwide were reported. [2]

According to the Global cancer data 2022:

Type of cancer Estimated new cases Estimated deaths

Breast cancer 287,850 43,250

Pancreatic cancer 32,790 23,860
Lung cancer 117,910 68,820
Ovarian cancer 65,950 12,181
Prostate cancer 268,490 34,500

Table1. GLOBAL CANCER DATA 2022

Treatment of cancer available to date includes chemotherapy, radiation therapy, bone
marrow transplant, immunotherapy, hormone therapy, targeted drug therapy, and
cryoablation. There are some drawbacks of cancer treatment which include
complications in targeting cancer stem cells, lack of specificity, the potential of
recurrence of tumor, lack of epigenetic profiling of cancer and specificity of epi-
drugs, cost ineffective, and development of drug resistance of tumor cells that
decreases the anti-tumor efficiency of therapeutic agents [3]. To overcome these
difficulties, there is a need for the development of novel therapies and new anti-cancer
drugs. That’s why drug repurposing came as a recent advancement in the cancer
world with the advancement in genomics, proteomics, and the computational world.

Drug re-purposing is a strategy for identifying new therapeutic uses for existing FDA-
approved drugs. It is also known as drug repositioning, therapeutic switching, drug re-
profiling, and re-tasking. Reasons for repurposing of the drug: reduces the risk of
disintegration, no human trials are needed, lower risk of failure, shortens the time
cycle of the drug development process, higher success rate, less investment,
understanding of mechanisms of action and molecular targets, knowledge about
toxicity and safety, availability of clinical experience and data [4,5]. Napolitano.et.al.
demonstrated the cost of the drug re-purposing process is less than 60% of
expenditure in traditional drug development. [6]

The re-purposing of the drug process involves the selection of a drug that has to be
repurposed based on the availability of the drug as a generic or off-patent, availability
of clinical experience data and case reports, availability of knowledge of safety and
toxicity of effect, efficacy evidence, reasonable mechanism of anti-cancer activity and
its interactions with the target, widespread availability of the drug in WHO Essentials
Medicines List [7]. After the selection of the drug, computational testing is performed
for its effectiveness, novel activity, and potent targets i.e., protein or pathway.
Recently, Insilico screening or an experimental approach is used for structural and
ligand-based drug design. Target-based, pathway-based network-based and
mechanism of action on targets are the different methods used for screening drugs for
repurposing [8]. Clinical development is also known as drug development, which
involves product development, pre-clinical or clinical trials for testing the safety of a
drug in humans and lastly, FDA-approved marketing of the drug is done. The
repurposed drugs can be used as monotherapy, chemo-protective agents or to enhance
the efficiency and roles of chemotherapeutic agents [9]. Anti-cancerous drugs or anti-
neoplastic drugs are anti-metabolite, tyrosine-protein kinase inhibitors, alkylating
agents, hormones or hormones antagonists, proteosome, angiogenesis, and EGF
receptors inhibitors. Different repurposed drugs used in cancer treatment are reported:
metformin, cyclophosphamide, disulfiram, nelfinavir, dexrazoxane, artemisinin,
mibefradil, doxorubicin, everolimus, and quinacrine [10].

Libby, G. et al. reported that repurposing drugs for cancer treatment resulted in a 37%
reduction in cancer incidence [11]. Bonovas S. et al. reported in a meta-analysis of
postoperative mortality in cancer patients having preexisting diabetes that the
presence of diabetes in cancer patients is 8% to 18%, showing a bidirectional
relationship between both diseases [12, 13]. Cyclophosphamide [cytoxan] is an
alkylating agent used as an anti-rheumatic drug that is repurposed to treat breast, and
blood cancer. It has cytotoxic effects due to its cross-linking ability to DNA and
inhibits protein synthesis. Hydralazine, a hypersensitivity drug used in cervical and
ovarian cancer, is in phase 3 trials. Thalidomide is a drug used in the treatment of
treating morning sickness in women with activity used in myeloma treatment.
Disulfiram [antabuse] used to treat alcoholism is in the progress of testing with copper
in the treatment of breast cancer. Nelfinavir is a protease inhibitor used to treat HIV
which is in 1 phase trial for treating lung cancer. Artemisinin is an antimalarial drug
used in breast cancer treatment as it arrests the cell cycle.

Mechanism of action of the repurposed drug during cancer treatment: activation of

protein kinase [AMPK] that inactivates mammalian target of rapamycin [Mtor],
Cyclooxygenase-2 [COX2], and phosphatidylinositol-3-kinase [PI3K] which leads to
change in the level of reactive oxygen level [ROS] and mitochondrial functions
inhibits. It also induces ferroptosis of SLC7A11 by inhibiting UFMylation leading to
cell death regulation [14]. The recent focus is to detect the effect of the drugs on
vascular functionality, maturity, and angiogenesis which is a hallmark cancer. The
expression of p53 and NRF2 as the upstream regulators of SLC7A11 and their roles in
the regulation of ferroptosis can be a direction for further research in the future.
FIG.1: DIFFERENT REPURPOSED DRUGS IN CANCER TREATMENT

1. BREAST CANCER:

Category of drug Name of repurposed drug Mechanism

Alkylating agent Cyclophosphamide Inhibits DNA replication

Anthracyclins Doxorubicin DNA intercalation
Antimetabolite Fluorouracil, methotrexate, Incorporate false building
gemcitabine blocks during cell growth
CDK 4/6 inhibitors Palbociclib, palbonix Cell cycle interference
HT-SERM Tamoxifen, raloxifene Binds to ER

Table 2. Different repurposed drugs for BC

It is the second leading cancer in the world leading to 2.3 million women dying
globally. It is characterized by its 4 types based on the presence of estrogen,
progesterone receptors, and human epidermal receptors 2[HER2]: [i] ER/PR+,
HER2+ [ luminal B subgroup] [ii] ER/PR-, HER2+ [ iii] ER/PR+, HER2- [Luminal A
subgroup] [iv] ER/PR-HER, 2-. Out of these, ER/PR-, HER2- [known as triple-
negative breast cancer, TNBC] is the most aggressive breast cancer because there are
no receptors present on these tumors [15, 16].

ER-positive BC reported 80% of all types of cancer and PR-positive accounts for 65%
of the total. 20% of the BC over-expressed HRR2. It is reported that 70 % of breast
cancer are hormone receptor-positive known as luminal breast cancer. The Luminal A
subgroup is determined by estrogen-receptor [ER] and progesterone-receptor [PR]
and the absence of HER2. The Luminal B subgroup is characterized by high
expression of Ki67, MKI67, or HER2 and has poor prognosis than luminal A [17, 18].
HER2+ BC leads to the over-expression of HER21ERBB2 oncogenes. HER2- is
characterized by mutation of APOBEC3B [a subclass of cytidine deaminases
APOOBEC which induces mutation of cytosine]. Pathological and molecular
characteristics of breast cancer are p53, Ki67, CA153, CEA, BRCA1/ BRCA2 [19].

TNBC is divided into 6 sub-types based on gene expression profile: basal- like1
[BL1], basal-like2 [BL2], luminal androgen receptors [LAR], mesenchymal [M],
immunomodulatory [IM], mesenchymal stem-like [MSL] [20]. Pathophysiology of
BC: BC is characterized by both invasive and non-invasive types. The non-invasive
subtype includes lobular and ductal carcinoma in situ while an invasive subtype
includes lobular and ductal carcinoma. 80% of ductal carcinoma cases are reported in
females. 5-10% of lobular carcinoma cases are reported [21]. The infiltration of T
cells in invasive BC and mostly the activated CD4+Th1 polarized cells secret
inflammatory cytokines which leads to upregulation of the MHC1 and MHC2 class
molecules which is an essential part of immune-mediated anti-tumor effects.
Activation of Th2-polarised CD 4+ T-helper cells results in the expression of
inflammatory cytokines [IL4, IL5, IL6, IL10, and IL13] that enhanced the humoral
immune responses and reregulate cell-mediated anti-tumor immunity which promotes
pro- tumor humoral responses [22,23].

Bicalutamide is the first drug that’s repurposed for the treatment of AR-positive
TNBC and induces cell apoptosis in MDA-MB-453 and MDA-MB 231 breast cancer
cells. Recently, Metformin [MET] is an anti-diabetic drug used in the treatment of
diabetes millets type 2 patients which are repurposed as a potential anticancer agent
that decreases the stimulated effects of insulin in breast cancer cells. Breast cancer
expresses high levels of insulin receptor that increases insulin circulation, which is
associated with breast cancer recurrence and death. The mechanism involved in the
anti-tumor action of metformin involves both direct [insulin dependent] and indirect
[insulin independent]. Luengo.et.al suggested that hepatic expression of AMPK and
upstream kinase LKB1 may be not required for suppression of gluconeogenesis
formed by metformin in mice models [24]. An AMPK-independent mechanism
involving glucagon activates adenylyl cyclase, leading to cAMP production and
stimulating cAMP-dependent protein kinase [PKA] signaling. Activation of PKA
decreases the level of fructose-2, 6, -bis-phosphate which favors gluconeogenesis in
the liver and increases the level of glucose in the blood. Metformin opposes the action
of glucagon due to the inhibition of the mitochondrial electron transport chain that
elevates the cytotoxic ratio of AMP: ATP ratio which stops cAMP production [25].
Madiraju.et.al. suggested that metformin also inhibits mitochondrial glycerol-
phosphate dehydrogenase [m GPD]. mGPD transports cytosolic reducing units from
NADH into mitochondria by the glycerol-phosphate shuttle pathway. Inhibition of m
GPD and mitochondrial complex1 reduces the ability of mitochondria to oxidize
NADPH of cytosolic which decreases the entry of reducing units into the electron
transport chain. It inhibits the proliferation of cancer cells by inducing cell cycle arrest
and apoptosis by regulating the expression of proteins that regulate G1-S cell cycle
transition i.e., cyclin E1, cyclin D1, and E2F transcription factor1 [26].
Cyclooxygenase [cox2] increases the production of prostaglandin E2 [PGE2] which
stimulates breast cancer progression. It also shows a chemo-protective effect by
regulating cytochrome P4501A1 [CYP1A1]/aryl hydrocarbons receptor [AhR]
pathways [27]. Wheaton WW.et.al suggested that metformin reduces the stabilization
of hypoxia-inducible factor alpha [HIFs α] and reduces the expression level of target
genes in tumors. Metformin also inhibits the mTOR signaling pathway. Rapamycin is
a specific inhibitor of m TOR which inhibits cap-dependent translation. mTOR
regulates mRNA translation by phosphorylation of its 2 main targets: 4E-BPs and
ribosomal protein kinase S6 [rpS6] kinase [S6K1/S6K2].
FIG2: MECHANISM OF METFORMIN BY FERROPTOSIS : Metformin downregulates
the SLC7A11 protein expression that leads to the repression of UFMylation
modification by UFM1, suppress GSH and GPX4 and increased lipid peroxidation
which induces ferroptosis in an AMPK-independent way.

Hyper phosphorylated 4E-BP1 binds to e1F4E which prevents the formation of e1F4F
this inhibits cap-dependent translation. Phosphorylation of S6K1 by mTOR enhances
the kinase activity of their downstream targets i.e., 40SrpS6, e IF4B, and
S6K1Aly/REF-like target. AMPK [heterotrimer serine/threonine protein kinase]
affects m RNA translation by inhibiting mTOR by phosphorylation and activation of
tuberous sclerosis complex 2 [TCS2] and sub-unit of TCS1/TCS2 complex [hamartin,
tuberin] which regulates m TOR signaling negatively. Hence, inhibition of mTOR by
activation of AMPK could be a new approach for the treatment of breast cancer [28,
29]. It suppresses the proliferation of breast cancer cells by increasing SCRIB [a cell
polarity protein] expression and cell membrane localization that increases SCRIB
interaction with MST1 and LATS1which inhibits transcription activity and nuclear
localization of YAP and TAZ. It leads to increased expression of KIBRA and
FRMD6, which activates the hippo pathway [30].
 FIG.3: MECHANISM OF ACTION OF METFORMIN : Metformin has potential to
reduce the level of insulin/IGF1 which is used in treatment of BC. It is transported
into cell by organic cation transporters [OCTs] and toxin extrusion[MATE] or the
transporters’ multidrug from the cell. Metformin activates AMPK and AMPK
dependent effects [ direct or insulin-independent effects] inside the cell. This involves
the inhibition of phosphorylation of IRS1, blocks MAPK and m TOR signalling
pathways. Metformin inhibits mitochondrial complex1 of electron transport chain that
decreases the level of ATP and increases ratio of AMP/ATP that activates AMPK.

2. OVARIAN CANCER:

It is the fifth most common cancer in women. Ovarian cancer (OC) results in 239,000
new cases and 152,000 worldwide deaths annually. Almost all benign and malignant
tumors are derived from three cell types: epithelial cells, stroma cells, and germ cells.
More than 90% of OC are epithelial-derived, 5%-6% are sex cord-stromal tumors
[i.e., granulose cell] and 2%-3% are germ cell-derived tumors. Malignant OC is also
known as carcinomas which consist of five main histotypes: high grade-serous
[HGSOC, 70%], endometrioid [ENOC, 10%], clear cell [CGCOC, 10%], mucinous
[MOC, 3%], and low-grade serous [LGSOC, <5%] [31, 32]. High- and low-grade
serous tumors originate from the epithelial of the Fallopian tube, CGCOC, and ENOC
is derived from cysts of endometriosis, and MOC is derived from transitional cell
nests of the mesothelial tubal junction. HGSOC and LGSOC are derived from the
tubal epithelium. All these 5 histotypes are thought to be progressed step-wise from
borderline tumors, characterized as Type I. Type II tumors showed an aggressive
phenotype and lacked a clear precursor. Type I tumors are linked with mutations in
genes BRAF and KRAS. PTEN gene mutations in endometroid tumors and HGSOC
tumors have p53 mutations predominantly [33]. The different drugs which are used to
treat OC are statins, metformin, bisphosphonates, ivermectin, itraconazole, and
ritonavir.

1. Statins: These are the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A

reductase [HMGCR] which is located upstream in the mevalonate pathway
that is involved in the biosynthesis of cholesterol [34]. It is used to reduce
cholesterol levels in plasma which is used in the treatment of cardiovascular
diseases. It can also influence vascular expansion and remodeling, inhibits
fibrinolysis and coagulation, and reduce inflammation. Li, X. et.al suggested
that the overall survival rate in OC patients is higher in statins users with a
hazard ratio =0.63[35]. Matiryosyan.et.al suggested that lovastatin triggers
apoptosis of OC cells by blocking the activity of HMGCR and blocking the
drug efflux pumps which sensitizes chemo-resistant cells to a doxorubicin
[mevalonate-dependent mechanism][36]. Dr. Richardson’s.et.al demonstrated
that pitavastatin which is a lipophilic statin has great potential in the treatment
of chemo-resistant tumors [37].
2. Metformin: It is used in the treatment of type 2 diabetes patients that inhibits
the respiratory-chain complex1 that mediates the activation of the liver kinase
and AMPK that increases ADP/ATP and AMP/ATP ratio, which leads to the
reduction in hepatic glucose output results in a reduction in proliferation of
cancer cells [38]. Hijaz.et.al suggested that metformin in combination with
cisplatin inhibits angiogenesis and cell viability, and induces apoptosis in OC
tumor cells [39]. The effect of metformin in combination with carboplatin-
paclitaxel chemotherapy in OC treatment is currently in phase 1 trial [40].
3. Bisphosphonates [alendronate, and zoledronic acid]: These are widely used
in the treatment of osteoporosis by bone resorption inhibition that decreases
the osteoclast activity. It blocks the fernery pyrophosphate synthase enzyme
which is necessary for maintaining the function of osteoclast. They block cell
proliferation and angiogenesis and promote apoptosis. Hashimoto, K. et.al
suggested that the alendronate drug reduces stromal invasion, ascites, and
tumor burden which is responsible for its anti-tumoral effect in OC [41].
Muinelo-Romay, L. et.al suggested that zoledronic acid has an anti-invasive
and anti-proliferative activity that leads to delayed recurrences in OC by
disturbing the steps of tumor dissemination [42].
4. Ivermectin: It is a polycyclic lactone pesticide produced by the bacteria
Streptomyces avermitilis which is a broad-spectrum antiparasitic agent that
binds to glutamic acid operative chloride ion channel present in muscle and
nerve cells. This binding increases the permeability of the cell membrane that
promotes the entry of chloride ions into the cell which results in
hyperpolarization of muscle and nerve cells and causes paralysis of the
parasite. It is widely used to treat onchocerciasis, lymphatic filariasis, and
scabies. It is used as an anti-neoplastic agent that targets yes-associated
protein1 [YAP1] as high expression of YAP1 is a prognostic indicator of OC
[43]. It also exhibits a karyopherin subunit beta1 [KPNB1] dependent anti-
tumor effect. Zhang, X. et.al represented that ivermectin suppresses the
phosphorylation of molecules involved in the Akt/m TOR signaling pathway
[44].
5. Itraconazole: It is a broad-spectrum antifungal agent that inhibits the
synthesis of ergosterol by blocking lanosterol14a-demethylase enzyme leading
to the destruction of the cell membrane of fungi. It targets different
oncological mechanisms: inhibiting Hedgehog, m TOR, and Wnt/β-catenin
signaling pathways, reversing chemoresistance mediated by P-glycoprotein,
inhibiting angiogenesis by inhibiting phosphorylation of ERK and vascular
endothelial growth factor receptor 2 [VEGFR2]. A combination of
itraconazole and paclitaxel can increase chemotherapeutic response in OC
patients [45]
6. Ritonavir: It is a protease inhibitor used to treat AIDS. It possesses anti-
proliferating activity in cells of OC by inhibiting the AKT pathway and
 inducing cell cycle arrest. Cheung, T.W. et.al reported that highly active anti-
retroviral therapy [HAART] is defined as a combination therapy in which
protease inhibitors i.e., ritonavir, and nelfinavir and reverse transcriptase
inhibitors i.e., zidovudine are used to decrease the risk of OC [46].

3. PROSTATE CANCER (PCA):

The prostate is a gland in males that is located between the penis and the bladder. It
produces seminal fluid which nourishes or transports sperm. PCA is a type of
adenocarcinoma in which neoplasia of glandular cells is detected. It is the second
leading cancer in men. The American Cancer Society 2021 reported 248,530 new
cases of prostate cancer and 34,130 deaths due to prostate cancer. PTEN gene
deletion is found in 16 -32% of PCA cases. Ras’s mutations facilitate epithelial-
mesenchymal transition [EMT], making PCA more aggressive. Tomlins S.A. et.al
reported that 40-80% of PCA is seen due to gene fusion of TMPRSS2-ERG
transcription factors [47]. HOXB-13 G84E is a gene variant responsible for
tumorigenesis of prostate cancer. The different repurposed drugs for the treatment of
PCA:

Lipid-lowering agents:

1. STATINS: These are the lipid-lowering agents that inhibit hydroxyl-3-methyl-

glutaryl-coenzymeA reductase [HMGCR] enzyme involved in the mevalonate [MVA]
pathway. Statins block the MVA pathway that affects YAP and tafazzin [TAZ]-
dependent transcriptional responses reduce the growth of cancer cells. Lovastatin and
simvastatin inactivate RhoA, arrest the cell cycle in phase, and induce apoptosis
mediated by cytochrome C-dependent and independent signaling pathways. They
lower the expression of p-Rb, Rb, CDK4, 6, and cyclin D1, and D3 but increase p27
and p21 in PCA cells [49].

Name of statins Mechanism of action Dose

Fluvastatin Down-regulating the 0-10 µM [in vitro]
phosphorylation of
FOXO1/AKT
Simvastatin Reduces PSA expression, 0-50µM [in vitro]
 inhibits MCL-1 and Akt
Atorvastatin Lowers the expression of 0-10µM [In vitro]
hypoxia-inducible factor
[HIF-1α], Bcl-2, p-Erk1/2,
p-Akt and activation of
NF-κB
Mevastatin, Rosuvastatin Inhibits the synthesis of 0-10µM [In vitro]
GGPP, induction of
transcription of light chain
3[LC3]
Lovastatin Inactivation of RhoA 0-2µM [In vitro]

Table 3. Different repurposed statins are used for prostate cancer treatment.

2. FIBRATES [FB]: It is a class of hypolipidemic medication which reduces

cholesterol [LDL] and TGs in the bloodstream. These drugs are peroxisome
proliferative-activated receptor alpha [PPAR-α] which has anticancer effects. FB
arrests the cell cycle in the G1 phase which downregulates E2F1 and cyclins D1,
decreased the level of Bcl-2, and increased the level of Bcl-2-associated x protein
[Bax] that leads to apoptosis [50].
FIG.4: MECHANISM OF ACTION OF FIBRATES: PPARα induces oxidative stress,
upregulates FoxO3A, FoxO1 and AMPK pathway and downregulates AKT
phosphorylation and ERK signaling pathway. It downregulates cyclins D1 and
E2F1 and Bcl-2, Bcl-xL and caspases3 that leads to apoptosis of cell.

Beta-Blockers: BBs are cardioprotective medications that showed antagonist

action by inhibition of β-adrenergic receptors. BBs are an effective therapy for
neuroendocrine prostate cancer [NEPCA]. Treatment by propranolol
downregulates the expression of markers of NE, inhibits angiogenesis, and
develops NEPCA cell-derived xenografts by disturbing the CREB1-EZH2-
TSP1 pathway [51]. Administration of propranolol l increases the level of
autophagy markers i.e., p62 and LC3-II.

FIG.5: MECHANISM OF ACTION OF BETA -BLOCKERS : Androgen derivation

therapy [ADT] increases the level of cAMP which activates PKA that leads to
CREB1 activation. Activation of CREB1 induces transcription of genes
responsible for angiogenesis and neuroendocrine differentiation [NED] i.e.,
VEGF [a pro-angiogenic factor], GRK3[promotes angiogenesis],
HDAC2[promotes angiogenesis], and ENO2[neuroendocrine marker]. GRK3
and HDAC2 downregulates TSP1[anti-angiogenesis factor] which promotes
angiogenesis. Activation of CREB1 increases the function of PRC2 of E2H2
which is important for NED and angiogenesis induced by ADT. VEGF leads
to the expression and activity of E2H2 promotes angiogenesis in endothelial
cells. Loss of p53 and RB1[tumor suppressor genes] promotes angiogenesis
and NE phenotype. Interaction of AURKA with N-Myc enhances NED.
AURKA and AURKB is responsible for angiogenesis regulation in
neuroblastoma and endothelial cells. HIF1A enhances angiogenesis by
inducing VEGF. ONECUT2 is known to be NED master regulator. Tyrosine
kinase RET is involved in the NED regulation and angiogenesis.
Heparin: It is an anticoagulant that exhibits antiangiogenic properties due to
structural changes in fibrin, inhibits the binding of ligands to VEGF receptors,
and inhibits the endothelial factor pathway. It has antimetastatic action by
blocking P-and L- selectin, regulating chemokines, and suppressing the
activity of heparinase. Hatziapostolou, M. et.al clinically reported that FGF2 is
related to the growth of malignant prostate and high levels of serum FGF2
present in patients of PCA [52].
FIG.6: MECHANISM OF ACTION OF HEPARIN : LMWH [low molecular weight
heparin] suppress VEGFR-3[vascular endothelial growth factor] phosphorylation that
inhibits lymphogenesis. It reduces the E-cadherin expression. P-selection is located in
α-granules of platelets and translocated onto the surface of the cell after activation.
Binding of P-selectin to P-selectin legend on the cancerous cell surface leads to the
formation of platelet-cancer cell complex which mediated the cancer cells adhesion to
the endothelial cells. Heparin leads to the blockage of this complex causes the
disruption of cancer cells adhesion to cells of endothelial and increase the level of
TNF-α [Tumor necrosis factor], an inflammatory cytokines which upregulates CCR7
that regulates the increased tumor cell migration. It causes the upregulation of IL-
8[interleukin-8], a proinflammatory chemokine causes angiogenesis. It causes the
downregulation of FX and FXa that are involved in cascade of the coagulation
decreases the formation of stroma of tumor. CP [cancer procoagulant], TP [ Tissue
factor procoagulant], FXa [activated factor Xa], and FX [coagulation factor X called
as Stuart factor].

Cardiac glycosides [CGs]: These are steroid-like structures used to treat

congestive heart failure [CHF], atrial fibrillation, and atrial flutter. Ouabain
[dose: 1-10µM] exhibits anticancer activity against androgen-independent PCA
that results in loss of activity of telomeric DNA. It arrests the cell in M or G2
phase by halting the functioning of cyclins and CDK-inducing apoptosis in PC3
 and C-42 cells. It also causes endocytosis of Na+/K+-ATPase and increased
expression level of cell cycle inhibitor p21 Cip. It downregulates the marker
STAT3 in a cancerous cell [53]. Oleandrin [dose: 0.001-0.002µg/ ml]
downregulates procaspase-3, activates PARP and caspases, and inhibits the
activity of NF-κ B [54]. Digitoxin [dose: 1-10µM] inhibits the synthesis of HIF-
α and decreases the expression level of the HOXB-13 gene. Digoxin [dose: 1-
10µM] induces differentiation of CAF and inhibits the expression of TGFβ.

FIG.7: MECHANISM OF ACTION OF CARDIAC GLYCOSIDES : Binding of cardiac

glycosides to the preassembled Na+/K+-ATPase [NKA] pump signalosome in
caveolae transduce signals. NKA activation leads to Src tyrosine kinease activation
that further activates EGFR. Activated EGFR engages protein adaptors which leads to
the activation of RAS-GTP complex that activates MEK pathway. Activation of
MAPK [mitogen-activated kinease] results in the opening of ATP-sensitive potassium
channels of mitochondrial, results in the activation of NKⱪB and increased production
of ROS that leads to phosphorylation of JNK results in increase in the level of BAX.
Src regulates the activation of PI3K/PDK1 pathway parallelly that results in
phosphorylation of AKT pathway that leads to apoptosis. NKA activates inositol-
1,4,5-triphosphate [IP3] and phospholipase [PLC] which binds to endoplasmic
reticulum and releases calcium ions into cytoplasm. This oscillation of calcium
activates PKC and NKⱪB. CGs results in the upregulation of caspase 3 that leads to
apoptosis.

RAAS [rennin-angiotensin-aldosterone] inhibitors: Angiotensin2 [ANG2] is the

main bioactive peptide out of all intermediates of the RAAS cascade. Captopril
lowers the incidence of PCA by crossing the blood-seminal plasma barrier and lowers
the level of DNA damage marker 8-hydroxydeoxyguanosine. Enalapril is an ACE-I
that downregulates transcriptional factor NF-κ B and VEGF m RNA [55].

4. LUNG CANCER:

The lungs are the most typical organ for cancer to spread in the body. This is because
blood flows back to the heart from different body parts and then enters the lungs.
Cancer cells that are present in the bloodstream remain in the capillaries of the lungs.
Sigel, R.L. et.al suggested that lung cancer causes 1670 deaths per day in 2023[56]. It
has the second-highest incidence of cancer with 238,430 new cases and an 81%
mortality rate in 2023. According to the National Institute of Health, the U.S. reported
that the 5-year survival rate for lung cancer is 56% when the disease is still localized
[intrapulmonary] and 16% of lung cases receive an early diagnosis. The 5-year
survival rate for distant tumors is 5% which suggested that the survival rate of lung
cancer is low as compared to other types of cancer. Lung cancer is categorized into
two types: small cell lung carcinoma [SCLC] with 15-20% cases and non-small cell
lung carcinoma [NSCLC] with 80% cases. NSCLC subtypes include adenocarcinoma,
squamous, adenosquamous, spindle cell, large cell, pleomorphic, and giant cell
carcinomas. Adenocarcinoma is the most common subtype of NSCLC and measures
60% of lung cancer cases [57]. Hanna, J.M. et.al reported the inflation in the
population of BASC [a subset of distal adult lung epithelial stem cells] associated
with tumor progression in KRAS-mutant mice [58]. The epidermal growth factor
receptor [EGFR] gene is the most important cancer-related gene which affects
NSCLC. MET gene codes for tyrosine kinase receptors associated with lung cancer
metastasis and pathogenesis. EML4-ALK [a lymphoma kinase gene] and KRAS
[Kristen rat sarcoma viral oncogene homolog genes] is the gene responsible for
adenocarcinoma. Fibroblast growth factor receptor type 1[FGFR1] gene and discoidin
domain receptor 2 [DDR2] gene codes for tyrosine kinase cell surface receptor is
responsible for squamous cell carcinomas by 20% [59, 60, and 61]. The repurposed
drugs used for the treatment of NSCLC are as follows:

1. Beta-blockers: These are anti-hypersensitive and anti-arrhythmic drugs.

Sidorova.et.al studied the beta-blocker effect on the viability and colony formation of
NSLC cells, revealing that propranolol and betaxolol are the most responsive in the
colony formation of lung cancer cells at 90% of EC50 value [62]. Propranolol
decreases angiogenesis of the tumor and makes β receptors insensitive towards the use
of chronic β-agonist which increases the expression of IL-6 stimulating the
proliferation of cells and inhibits liver kinaseB1 [LKB1] tumor suppressor in EGFR-
positive adenocarcinoma lung tumors. Angiotensin I converting enzyme inhibitors
[ACEIs] and angiotensin II receptor blockers [ARBs] are repurposed for the treatment
of NSLC because the renin-angiotensin-aldosterone system is the major hallmark of
cancer [63]. Telmisartan and losartan are ARBs that activate PPARγ resulting in the
cessation of metastasis of the tumor. Godugu, C. et.al reported that telmisartan had
2.7-fold greater intratumoral distributions as compared to losartan [64].
2. Nonsteroidal anti-inflammatory drugs [NSAIDs], Anti-inflammatory drugs:
These inhibit Cyclooxygenase [COX] enzymes. Upregulation of COX2 is seen in lung
adenocarcinomas. The specific inhibitor of COX2 is Celecoxib used as an anti-
analgesic for rheumatoid arthritis and osteoarthritis. Celecoxib helps in the down-
regulation of NF-κ B, BAX, caspases-9, and BCL-X. It binds to 3-phosphoinositide-
dependent protein kinease-1[PDK-1] which inhibits the PDK1/Akt pathway that
controls the coupling of nucleus-centrosome and regulates the binding of MAP to
microtubules [65]. Indomethacin is an NSAID that inhibits COX-2 enzyme inhibitors.
Sarvepalli.et.al prepared IND liposomal formulations to enhance its potential of
anticancer by inhibiting the enzymatic activity of caspases-3 by upregulation of the
Bax, Bak, and PPAR-γ pathway [66].
3. Anti-hyperlipidemic drugs: Statins are used as repurposed drugs for lung cancer
treatment. Statins inhibit the enzyme β-hydroxy β-methylglutaryl-CoA [HMG-CoA]
which is essential for the synthesis of cholesterol. They also decrease the production
level of mevalonate derivatives which are important for cell proliferation and
differentiation. Atorvastatin is a statin that results in the inhibition of Akt/m TOR and
activation of the MAPK pathway. It also leads to the depletion of isoprenoid-derived
growth proteins which are important for the cell-growth-stimulating proteins [Rac,
Rho, and Ras] functioning [67]. Hosseinimehr.et.al reported that the apoptosis rate of
both atorvastatin and irradiated treated A549 lung cancer cells was higher than that of
irradiated cells alone [68]. Lovastatin increases the expression of COX2 and activates
PPAR-γ which induces cytotoxicity in the cancerous cell of the lungs. Simvastatin
induces apoptosis in mutated cells with p53. Gefitinib plus simvastatin showed a
higher response rate in treating NSCLC as compared to gefitinib in 2 nd phase trials
[69]. Pitavastatin in combination with erlotinib showed a collaborative cytotoxic
effect on the EGFR-TKI-resistant lung adenocarcinoma human cell line that inhibits
the mevalonic acid pathway and pan-caspase inhibitor z VAD [70].
4. Anti-malarial drugs: Atovaquone inhibits the consumption of mitochondrial
oxygen that decreases tumor hypoxia in NSCLC patients. Dihydroartemisinin causes
NSCLC metastasis inhibition by modulation of glucose metabolism and inhibits the
NF-κ B pathway [71]. Quainacrine leads to the FACT resistance [facilitates chromatin
transcription complex which is involved in tyrosine kinase inhibitor [TKI]. Bhateja, P.
et.al suggested that erlotinib and quinacrine combination in a phase 1 clinical trial for
the treatment of NSCLC [72].
5. Anti-retroviral drug: Lopinavir is a protease inhibitor used in combination with
ritonavir used for lung cancer treatment by arresting the cell cycle, decreasing cell
viability, and apoptosis the cell. Nelfinavir inhibits the proteasome's activity in the
lung's cancerous cell. Efavirenz has been shown a coordinative effect in combination
with radiation therapy for lung cancer [73].
6. Anti-helminthic drugs: Mebendazole showed cytotoxic effects on NSLC cell lines
A549, H1299, and H460 by blocking the polymerization of tubulin leading to the
inhibition of synthesis of the microtubule. It leads to the downregulating expression of
MDM2 and p21. Ozdemir, A. et.al reported that a niclosamide and piperazine hybrid
also exhibits anti-proliferative properties on the cancerous cell of the human lung in
vivo [74]. Ivermectin exhibits antineoplastic properties by blocking the canonical
WNT [wingless-related integration site] signaling pathway which affects the T-cell
factor [TCF] family transcriptional factor [75].
7. Other drugs: Sertraline is an antidepressant used in combination with erlotinib for
the treatment of lung cancer which results in the AMPK/m TOR pathway in cells of
NSCLC. Nitroglycerin is a nitric oxide [NO] donner used in the treatment of angina
but also downregulates HIF1 alpha and inhibits angiogenesis. The combination of
vinorelbine and cisplatin with nitroglycerin is in the IInd phase of the clinical trial
suggesting that the survival rate of the untreated stage of IIIB/IV non-squamous cell
lung cancer has been improved [76].

5. PANCREATIC CANCER:
PC starts in the cell lining of the pancreatic duct known as pancreatic
adenocarcinoma. Pancreas is an organ that lies behind the lower part of the stomach
that helps in the metabolism of sugars. PC is late detected, rapidly spreads, and has a
poor prognosis with less than 8% of the 5-year survival rate. According to the
American Cancer Society, PC is found in 64,050 people and 44,330 deaths with a
12% increase in the 5-year survival rate. Street, w. et.al reported that PC will be the
second leading cause of cancer death by 2023. It remains a difficult disease to treat
because of its aggressive nature, early metastasis to distant and nearby organs,
delayed clinical presentation, and inherent resistance to current treatment. 85% of
cases of PC are exocrine pancreatic in origin. Mutations in KRAS [90%], CDKN2A
[90%], TP53 [70%and], and SMAD4 [55%] genes are responsible for the occurrence
of PC [78]. CCAT2 gene [long non-coding RNA] is an oncogene responsible for
PDAC. Shin SH, et.al reported SMAD4/DPC4 gene in 641 patients of PC. EGF,
EGF-R, HER-2/neu, and p185 overexpression led to the advanced stage of PC.
Hypermethylation of RARb, p16, CACNAIG, TIMP-3, Ecad, THBSI, Hmlh1, DAP
kinase, and MINT31 are also responsible for the occurrence of PC. RASSFIA [75%],
Inka/p16 [40%], OMGMT [40%], O-MGMT [40%], RAR-B [25%], GSTπ, E-
cadherin, APC, P14ARF genes Hypermethlyation are associated with pancreatic
neuroendocrine tumors at an advanced stage of the tumor [79]. The different
repurposed drugs for PC treatment are as follows:
1. Auranofin: It is an organogold complex containing an Au-S bond stabilized by
the triethyl phosphine group used for the treatment of rheumatoid arthritis. It exhibits
antitumor action by inhibiting hypoxia-inducible factor-1α, accumulation of
mitochondrial ROS, activation of caspase 3/7, and cleavage of proteolytic PARP.
Kshattry S, et.al demonstrated the cytotoxicity of cancer cells by treatment with a
combination of depletion of L-Cys extracellular pool and oxidative stress [80].
2. Anti-psychotic drugs: Haloperidol and penfluridol are hydroxypiperidines that
block the dopamine D2 receptor [DRD2] which promotes stress in ER. It promotes
DUSP6 gene demethylation in MIA PaCa-2 cells. Jandhagi. et.al reported that the
expression level of DRD2 is increased in PDAC [81]. Penfluridol activates protein
phosphatase2 [PP2A] that inhibits PC tumors. It targets the binding site of JAK2 in
PRLR which suppresses ERK/AKT and JAK2-STAT3 signaling pathway.
3. Disulfiram: It is a derivative of organic disulfide by oxidative dimerization of N,
N-diethyldithiocarbamate acid used in the treatment of alcoholism. DSF leads to the
chelating of copper cations [Cu2+] which forms the DSF/Cu complex and acts as an
inhibitor of proteasome that results in the inactivation of NF-κ B. Han et.al reported
that diethyldithiocarbamate [DDTC], a DSF metabolite which forms a binuclear
complex DDTC-Cu[I] affecting the proliferation of PC cell by upregulating p27 and
downregulates the expression of NF-KB [82]. Disulfiram in combination with
chemotherapy is in phase 1 clinical trial for PC treatment.
4. Anthelmintic drugs: Niclosamide [Nic] exhibits anti-cancer properties by
arresting cell cycle in G0/phase. It also causes mitochondrial stress and mTORC1-
dependent autophagy. It inhibits BCL2 and Beclin-1interaction which leads to
apoptosis and autophagy. Nic leads to the inactivation of Gsk3β by Ser 9 residue
phosphorylation leads to Sufi and Gli3 upregulation which affects the hedgehog
signaling pathway negatively [83].
FIG.8: MECHANISM OF ACTION OF NICLOSAMIDE: Anti-cancer effect of Nic in
cells of PC by Gsk3β inactivation by inhibiting Ser-9 phosphorylation. Upregulation
of p-Gsk3β regulates Hh/Gli cascade and m TOR1-dependent autophagy signaling.
Upregulation of Sufu and Gli3 nuclear accumulation with Gli1 downregulation
simultaneously which inhibits signalling of Hh that results in the PC cell proliferation
inhibition.

5. Antiviral drugs: Efavirenz, ritonavir, and nelfinavir are the HIV inhibitors used
for the treatment of PC. Efavirenz results in the production of ROS, depolarization of
the membrane of mitochondria, ERK1/2, and p38 MAPK stress pathway
phosphorylation in PC cells. Nelfinavir inhibits the phosphorylation of the AKT/PI3
signaling pathway and is in the IInd phase of a clinical trial. Batchu. et.al reported that
ritonavir suppresses the phosphorylation of Rb.

CONCLUSION: The drug re-purposing method can break the bottleneck of

remarkable drug shortage. Nononcology drug production and use have always been
the expansion of medication. Many of the arbitrary findings are a boon for the re-
purpose of the drug. The process of de novo research is costly and long term whereas
the re-purposing of the drugs reduces investment and time for a specific therapeutic
purpose. The treatment of TNBC has an absence of targeted therapy due to its
complexity in intrinsic molecular and histopathology which decreases the chance of
recovery in patients and the expectancy of life. The therapy with different molecular
targets is being investigated currently including adrenergic and androgen receptors,
nitric oxide synthase, STAT3, and AXL-directed therapy for re-purposing in TNBC.
Herein is being studied for the treatment of TNBC currently. Zoledronic acid,
chloroquine, and L-NMMA are currently in the clinical stage for TNBC treatment. In
the case of OC, tumor cells present in ascitic fluid provide a platform to study the
efficacy of drugs in vivo in a personalized manner. Gene co-expression network
analysis is used for the identification of effective candidate drugs for treatment in
NSCLC. A combination of PCSK9-neutralizing antibodies with immune checkpoint
blockade can be further explored for PC treatment. Nononcology drugs that target
complex, multiple, and interthread pathways of cancer should be explored and
repurposed with current therapies to control metastasis in a better way. Drug re-
purposing is an attractive strategy that is worth exploring in the treatment of cancer.
James’s black [Nobel laureate in physiology and medicine] said that: “the most
fruitful basis for the discovery of a new drug is to start with an old drug [84].’’

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