Endophytes from Malaysian Medicinal

Plants as Sources for Discovering 10

Anticancer Agents

Ling-Sze Yap, Wai-Leng Lee, and Adeline-Su-Yien Ting

Abstract
Malaysia hosts a diverse range of medicinal plants having therapeutic values
including anticancer properties. Over the years, a group of microorganisms
called endophytes producing bioactive compounds similar to their host plants
has been discovered. These endophytes, producing important compounds such as
Taxol, L-asparaginase, and sclerotiorin, can be isolated and cultured in large
scale to produce valuable compounds. This alternative approach of producing
bioactive compounds is more sustainable than plants, as endophytes are renew-
able sources. In this chapter, endophytes from Malaysian medicinal plants have
been discussed, highlighting the diversity of endophytes, the valuable com-
pounds produced, the current methods used in biosourcing of endophytes, and
the future prospects of anticancer agents derived from endophytes of Malaysian
medicinal plants.

Keywords
Anticancer • Bioactive compounds • Endophytic fungi • Malaysian medicinal
plants • Natural products

Contents
10.1  Introduction  315
10.2  Endophytes from Medicinal Plants  317
10.3  Anticancer Agents Derived from Endophytes from Malaysian Medicinal Plants  320
10.4  Malaysian Marine Plants as Source of Endophytic Fungi  322
10.5  Biosourcing for Endophytes Producing Anticancer Compounds  323

L.-S. Yap • W.-L. Lee • A.-S.-Y. Ting (*)

School of Science, Monash University Malaysia,
Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia
e-mail: adeline.ting@monash.edu

© Springer Nature Singapore Pte Ltd. 2017 313

D.C. Agrawal et al. (eds.), Medicinal Plants and Fungi: Recent Advances in
Research and Development, Medicinal and Aromatic Plants of the World 4,
https://doi.org/10.1007/978-981-10-5978-0_10
314 L.-S. Yap et al.

10.6  M alaysian Medicinal Plants: Potential Hosts for Endophytes

Producing Anticancer Compounds  324
10.7  Conclusions and Future Prospects  330
References  330

Abbreviations

A549 Human Caucasian lung carcinoma

B16-F10 Mouse skin melanoma
CDK Cyclin-dependent kinase
CEMss Human T4-lymphoblastoid cell line
CPT Camptothecin
D551 Human normal skin cells
DLD-1 Human colorectal adenocarcinoma
DNA Deoxyribonucleic acid
ELISA Enzyme-linked immunosorbent assay
HCT116 Human colon carcinoma
HeLa Human cervix carcinoma
HepG2 Human Caucasian hepatocyte carcinoma
HPLC High-performance liquid chromatography
K562 Human chronic myeloid leukemia
Kb Oral carcinoma cells
LLC Lewis lung carcinoma
M059J Human brain malignant glioma
MCF-7 Human breast adenocarcinoma
MCM-B2 Canine mammary carcinoma
MDAMB231 Human breast adenocarcinoma
MG63 Human bone osteosarcoma
MS Mass spectrometry
MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NCI-H1299 Human lung carcinoma
NMR Magnetic resonance spectroscopy
NPAA Nonprotein amino acids
P388 Murine leukemia cells
PBLs Primary blood lymphocytes
PC12 Rat adrenal pheochromocytoma
PC3 Human prostate adenocarcinoma
SkO-3 Human Caucasian ovary adenocarcinoma
T-47D Human breast ductal carcinoma
TCM Traditional Chinese medicine
WEHI-3 Mouse leukemia cells
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 315

10.1 Introduction

Cancer is the world’s leading disease affecting as many as 3500 per one million
population in the world annually (Pandey and Madhuri 2009). Cancer is character-
ized by uncontrolled cell division, which results in abnormal cell growth. These
abnormal cells spread and metastasize to distant parts of the body, resulting in the
formation of malignant tumor cells and destroying normal healthy cells (Pandey and
Madhuri 2009; Madhuri and Pandey 2009; Prakash et al. 2013). The risk of cancer
occurrence in individuals increases with age, due to higher susceptibility toward
DNA mutation (Garinis et al. 2008). Various therapeutic measures have been used
to treat cancer including surgery, chemotherapy, and radiation therapy. Nevertheless,
these treatments are sometimes invasive and have numerous side effects, with the
main concern that the healthy cells are also destroyed. As a result, alternative cancer
treatments are explored.
Alternative cancer treatments are primarily focused on the use of medicinal or
herbal plants. These plants are rich sources of anticancer agents, as they have long
been known to have ethnobotanical properties related to the treatment of various
diseases. In the early civilization, herbal knowledge was practiced by referring to
Ebers Papyrus, “Shennong Ben Cao Jing,” and Atharva Veda and Rig Veda, from
Ancient Egypt, China, and India, respectively (Petrovska 2012). As modern medi-
cines were discovered, the role of medicinal plants was relegated to being cheaper
alternatives and used only where modern medicines are too costly. Nevertheless, in
the last few decades, the limitations of modern medicines, particularly the side
effects and drug resistance observed in clinical drugs, have led to the resurgence of
the use of traditional medicinal plants as possible alternatives (Lin et al. 2012).
Traditionally, medicinal plants are consumed or used to extract beneficial com-
pounds. For consumption, capsules and tablets containing raw, dried herb or their
powdered forms are often used. For extraction, beneficial compounds are extracted
using alcohol (tinctures), vinegar (acetic acid extracts), hot water (tisanes or decoc-
tions), or cold water infusion (macerates) (Benzie and Wachtel-Galor 2011). Despite
the many benefits and multiuse of these extracts, the levels of bioactive compounds
present in the plants are relatively inconsistent (Brusotti et al. 2014). This impacted
the wider use of medicinal plants for therapeutic purposes. In addition, the biosafety
of medicinal plants was also of concern with reports of heavy metal contamination
in medicinal plants (Drew and Myers 1997; Bent 2008). It is evident that despite the
many uses of medicinal plants, useful lead compounds are best elucidated through
intensive screening, extraction, purification, and quantification processes.
Plants generally produce two types of metabolites; the primary and secondary
metabolites. Primary metabolites, also known as central metabolites, are widely
distributed and can be found in almost all plants. These metabolites are involved in
plant growth and metabolism, usually playing an important role in maintaining the
physiological functions of a plant (Balandrin et  al. 1985). Examples of primary
metabolites are alcohols, amino acids, carbohydrates, and lipids. Secondary metab-
olites, on the other hand, are the end products or compounds derived from the pri-
mary metabolites. These compounds are not found in all plants and are limited to
316 L.-S. Yap et al.

Table 10.1  Examples and number of known secondary metabolites of various classes from plants
Number of known
Class secondary metabolites Examples
Alkaloids 21,000 Cocaine, morphine, atropine, nicotine
Nonprotein amino acids 700 Azatyrosine, canavanine
(NPAAs)
Cyanogenic glycosides 60 Amygdalin, prunasin, linamarin
Amines 100 Hordenine
Flavonoids, tannins 5000 Tannic acid, luteolin
Terpenoids >22,000 Artemisinin, tetrahydrocannabinol,
azadirachtin
Carbohydrates, organic 200 Stachyose, gentianose
acids
Adapted from Wink (2010)

the certain taxonomic group. Secondary metabolites do not have a specific function
as they are not involved in the plant metabolism, but they do contribute to the host
plant defense system. They also contribute as lead compounds with therapeutic
functions, produced typically as a response by the medicinal plants to various biotic
and abiotic stresses (Bernhoft 2010). Plant secondary metabolites can be classified
into two major chemical groups: the nitrogen-containing metabolites such as alka-
loids, nonprotein amino acids (NPAAs), cyanogenic glycosides, and amines and the
non-nitrogen-containing metabolites such as flavonoids, tannins, terpenes, and car-
bohydrates (Table 10.1).
Some of these plant secondary metabolites have anticancer properties and have
been extensively studied and tested in clinical trials. Primary examples include the
discovery and the use of vinca alkaloids and paclitaxel (or Taxol). The vinca alka-
loids are derived from the periwinkle plant Catharanthus roseus. This plant pro-
duces vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine,
has antimitotic properties, and thus is highly effective for the treatment of lym-
phoma, leukemia, testicular cancer, Hodgkin’s disease, and lung cancer (Greenwell
and Rahman 2015). They induce cell cycle arrest and inhibit angiogenesis by bind-
ing onto the β-tubulin. This affects the dynamics of tubulin addition to the end of the
mitotic spindle, implicating cell proliferation in cancerous cells as the function of a
mitotic microtubule is hampered (Jordan et al. 1991; Umadevi et al. 2013).
In addition to vinca alkaloids, paclitaxel (Taxol) is another well-known antican-
cer medication used in chemotherapy. Paclitaxel is effective as it targets the tubulin,
stabilizing and promoting the polymerization of microtubules. This blocks the pro-
gression of cell division and finally triggers the occurrence of apoptosis (Horwitz
1992; Weaver 2014). Paclitaxel was first isolated in 1971 from the inner bark of the
Pacific yew tree (Taxus brevifolia) and sold under the brand name Taxol. Although
paclitaxel is a successful and effective anticancer agent, this anticancer agent is not
readily available to most cancer patients as it is extremely expensive. The high-cost
of paclitaxel is attributed to the scarcity of the yield of paclitaxel obtained from yew
trees. It has been estimated that 10,000 kg of yew tree bark can generate only 1 kg
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 317

of paclitaxel upon extraction (Chandra 2012). The low quantities of extracted pacli-
taxel and the slow growth rate of the yew trees account for the high price of pacli-
taxel in the market (Joseph and Priya 2011; Kharwar et al. 2011).
Also, it has been discovered that medicinal plants pose several limitations as a
feasible source for anticancer agents. Some medicinal plants are rare and slow
growing, in which they may require a longer duration to grow and reach maturity
and therefore requires several years or decades to be able to harvest the anticancer
agents from the plants. For some plants, the harvesting process can only yield a
small amount of anticancer agents. The low quantities of anticancer agents and slow
growth of medicinal plant will subsequently lead to the need to harvest more plants,
resulting in species extinction and environmental degradation. Several attempts
have been made to address issues on the low yield of anticancer compounds from
plants. For example, scientists have attempted to increase the harvest and extraction
of paclitaxel from plants by performing cell, organ, and tissue culture or to increase
the yield of paclitaxel through total and semisynthesis (Kharwar et al. 2011; Chandra
2012). The cell and tissue culture approach are, however, both costly and
time-consuming.
In 1993, paclitaxel was discovered for the first time from a non-plant origin and
endophytic fungus, Taxomyces andreanae. This endophyte was isolated from the
yew tree, which is the producer of paclitaxel (Gangadevi and Muthumary 2008).
With the discovery of T. andreanae as producer of paclitaxel, mass production of
this anticancer compound is achievable through batch culturing in the bioreactors.
This provides an alternative to producing more anticancer compounds in a cheaper
manner. Since then, several reports have been published on the production of Taxol
by different species of fungal endophytes. The discovery of endophytes producing
valuable bioactive compounds such as paclitaxel has opened new chapters in the
research of anticancer agents derived from endophytes.

10.2 Endophytes from Medicinal Plants

Endophytes can be defined as microorganisms, usually bacteria or fungi, which

reside in host plant tissues without any visible symptoms (Petrini 1991; Tan and Zou
2001). Endophytes are ubiquitous and can be found in most of the plant species and
throughout almost all plant tissues, including the leaves, stems, barks, roots, and
rhizomes (Raviraja 2005). Endophytes form an endosymbiotic relationship with the
host plant. The host plants provide protection and nutrients to the endophytes, and
in return, the endophytes benefit the host plants by promoting plant growth and
tolerance toward biotic and abiotic stresses (Tan and Zou 2001; Ting 2014).
Endophytes produce secondary metabolites that have anticancer, antimicrobial,
anti-inflammatory, antioxidant, antidiabetic, and immunosuppressive properties
(Joseph and Priya 2011). Some of the compounds produced by the endophytes are
similar to compounds produced by the host plants, such as in the case of paclitaxel
from T. andreanae, which showed similarities to paclitaxel from the host plant (yew
tree) (Gangadevi and Muthumary 2008). Chandra (2012) hypothesized that the
318 L.-S. Yap et al.

Table 10.2  Anticancer agents derived from fungal endophytes isolated from medicinal plants
Anticancer drug Endophytes Host plant References
Paclitaxel (Taxol) Taxomyces andreanae Taxus brevifolia Chandra
Pestalotiopsis Taxus wallichiana (2012)
microspora
Fusarium solani Taxus chinensis
Nigrospora sp. Taxus globosa
Phoma species Aloe vera
Alternaria sp. Ginkgo biloba
Colletotrichum capsici Capsicum annuum
Pestalotiopsis Taxodium distichum
microspora
Camptothecin Entrophospora Nothapodytes foetida Puri et al.
(CPT) infrequens Camptotheca acuminate (2005)
Botryosphaeria parva Nothapodytes nimmoniana Chandra
(2012)

production of similar secondary metabolites is due to the long-term coexistence and

close metabolic interaction between endophytes and host plants. Endophytes living
in tissues of stems and leaves of the host plants may have formed a strong symbiotic
association with the host plant over the long period of coexistence. This close rela-
tionship may have allowed genetic information to transfer between themselves and
the host plants, resulting in the generation of similar secondary metabolites in endo-
phytes as those from the host plant (Strobel 2003). Wang and Dai (2011) suggested
that endophytes produce a greater amount of bioactive compounds than their host
plants, with the presence of their biotransformation enzymes to change the three-­
dimensional conformation of bioactive compounds. Hence, endophytes are promis-
ing resources of bioactive compounds for anticancer or any other therapeutic
applications.
Of the many different compounds produced by endophytes, anticancer com-
pounds are highly sought after as alternatives to synthetic compounds in chemo-
therapy. Following the discovery of paclitaxel from the first Taxol-producing fungus,
Taxomyces andreanae, other endophytic species have also been reported to produce
Taxol. These endophytes are found naturally colonizing plants of the Taxus species
(T. yunnanensis, T. wallichiana, T. chinensis, T. globosa, T. cuspidata) and non-­
Taxus species (Taxodium distichum, Ginkgo biloba, Wollemia nobilis, Aloe vera,
Capsicum annuum) (Table 10.2). Each species of endophyte has a different capacity
of producing Taxol. Colletotrichum capsici from C. annuum and Pestalotiopsis ver-
sicolor from T. cuspidata reportedly have a relatively higher yield of Taxol (687 μg/l
and 478 μg/l, respectively). On the contrary, Tubercularia sp. isolated from T. chi-
nensis var. mairei (185.4 μg/l) and Phoma sp. from A. vera (73.66 μg/l) have a lower
yield of Taxol (Chandra 2012). Nevertheless, optimization of media and fermenta-
tion conditions are known to increase the production of Taxol (Xu et al. 2006).
Other than Taxol, camptothecin (CPT) is another anticancer compound pro-
duced by endophytes. Camptothecin is a pentacyclic quinoline alkaloid and is
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 319

typically derived from the bark and stem of the Camptotheca plant “happy tree”
from China (Kusari et al. 2012). CPT targets tumor cells by binding to the intra-
nuclear enzyme DNA topoisomerase 1 (Topo 1) and the DNA covalent complex,
stabilizing and preventing Topo 1 from swiveling and relaxing the DNA during
DNA replication and transcription. This deters the religation of DNA, leading to
DNA damage and apoptosis (Hsiang et al. 1989). Although CPT has a good anti-
cancer activity, the wide usage of CPT is hampered by poor solubility in aqueous
media, high toxicity, and the various side effects. Two of the analogues of CPT
from plants, 9-­methoxycamptothecin and 10-hydroxycamptothecin, are water sol-
uble, demonstrating potential anticancer activity as the CPT (Kusari et al. 2009).
Interestingly, high yield of CPT and its derivatives which are less toxic were found
in endophytes isolated from the host plants. Puri et  al. (2005) first reported the
production of CPT from the fungal endophyte Entrophospora infrequens, which
was isolated from the Sleumer tree (Nothapodytes foetida). CPT has also been
found to be produced by endophytes such as Fusarium solani, Nodulisporium sp.,
Neurospora sp., and Botryosphaeria parva from different host plants such as
Camptotheca acuminata, N. foetida, and Nothapodytes nimmoniana, respectively
(Table 10.2) (Chandra 2012).
Comparatively, bacterial endophytes are less dominant in producing anticancer
agents than the fungal endophytes. While the latter has a long list of species and
compounds produced (as discussed in the previous section and Table 10.2), the for-
mer has only several notable species known to produce anticancer compounds.
Most of the bacterial species capable of producing anticancer compounds are of the
Bacillus species, such as B. amyloliquefaciens, B. subtilis, and B. cereus, and
Lysinibacillus sp., which produce exopolysaccharide or camptothecin with antican-
cer potential (Chen et al. 2013; Shweta et al. 2013). These endophytes were isolated
from medicinal plants such as Ophiopogon japonicus (mondo grass or monkey
grass) and the climber plant Miquelia dentata Bedd. Taechowisan et al. (2007) also
discovered endophytic actinobacteria Streptomyces aureofaciens CMUAc130 from
the root tissues of Zingiber officinale. This isolate produces the bioactive compound
4-arylcoumarins and its derivative 5,7-dimethoxy-4-phenylcoumarin, which exhib-
ited significant anticancer activity toward transplanted Lewis lung carcinoma
(LLC). Liu et al. (2012) also documented the antitumor activities of levan-type exo-
polysaccharide (EPS) produced by Paenibacillus polymyxa EJS-3. This bacterium
is an endophyte found in the roots of Stemona japonica (or “Bai Bu” in Chinese), a
Chinese medicinal plant used to treat different types of cough illness. Future
research on discovering more bacterial endophytes and their anticancer compounds
will benefit the anticancer therapeutic field.
320 L.-S. Yap et al.

10.3 A
 nticancer Agents Derived from Endophytes
from Malaysian Medicinal Plants

The endophytes from Malaysian medicinal plants have been found to produce bio-
active compounds with anticancer activities. These endophytes are primarily iso-
lated from medicinal plants, while herbal plants, seaweed, or spices, such as ginger,
pandan leaf, hibiscus flower, lemongrass, and bay leaf, are also known to harbor
valuable endophytes (Radu and Kqueen 2002; Hazalin et  al. 2009). Radu and
Kqueen (2002) were among the first few researchers to document the antitumor
activities of endophytic fungi from Malaysian medicinal plants. In their study, 13 of
the 72 medicinal plants screened were hosts to endophytic fungi with strong antitu-
mor activities (Table  10.3). The antitumor activities from the endophytes were
detected using UCK/UCS yeast cell-based assay in which isolates that rescue the
growth arrest caused by the hyperactivation of cyclin-dependent kinase (CDK) were
considered to possess anticancer properties. In their preliminary study, an accurate
comparison of effective isolates was not achieved as crude extracts were used in the
bioassay. As such, the low antitumor activity may be due to the lesser amount of
bioactive compound obtained and the impurities present in the crude extracts.
Therefore it is not an accurate measure of bioactivity of the compounds. The species
of fungal endophytes and compounds, which demonstrated anticancer activities,
were also not further identified or characterized in their study.
Following the work by Radu and Kqueen (2002), Hazalin et al. (2009) explored
native plants from the National Park, Pahang, Malaysia. They isolated 300 endo-
phytic fungi from 43 different plants using the leaf, stem, root, and flower tissues.

Table 10.3  Summary of fungal endophytes recovered from Malaysian medicinal plants and their
antitumor activities using crude extracts
Local name of medicinal plant (scientific Antitumor activity (mm)
Endophytic isolates name) UCSa UCKb
5L Bisa ular (Barleria lupulina) 8 8.5
24L2 Kesum (Polygonum sp.) 8 8
50ML Tembaga suasa besar (Rinum aisiaticum) 10 10.3
b9L Cekur (Kaempferia galanga) 10 10.3
b14L Ervalanala (Aerva lanata) 8.2 8.2
b20L Jerangau (Acorus calamus) 7.5 7.5
b29L Lidah mertua (Sansevieria trifasciata) 8.3 8.1
b30L Mengkudu (Morinda citrifolia) 9 9
b34L Pandan (Pandanus odons) 7.2 7.1
b49L Sembong (Blumea balsamifera) 8.7 8.5
b53L Tongkat ali (Eurycoma longifolia) 8 8.1
b69L2 Sambung nyawa (Gynura procumbens) 8.1 8
b70L2 Serai kayu (Eugenia polyantha) 8.6 8.3
Based on data from Radu and Kqueen (2002)
a
UCS – Yeast test strain containing plasmid Yep51-SRX5
b
UCK – Yeast test strain containing plasmid mPR438-CyclinA D 24–62
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 321

Crude extracts were prepared and tested for cytotoxic activities against several can-
cer cell lines. It was discovered that a majority of the extracts were more effective
against the murine leukemia P388 cell line compared to the human chronic myeloid
leukemia cell line K562. They discovered that extracts from ten endophytic species
exhibited higher anticancer activity against P388 than the existing anticancer agents
from Paecilomyces farinosus (paecilosetin, farinosone) and Penicillium sp. GQ-7
(penicillenol). Hazalin et al. (2009) also discovered that the fungal endophyte strain
KK29FL1 isolated from the flower of Costus speciosus (spiral ginger or “setawar
hutan”) had the greatest cytotoxic activity against P388 and K562 cell lines. The
endophyte was identified as a Sporothrix sp., but the extract was not further
characterized.
The rain forests offer plants with promising potential to produce anticancer com-
pounds. Ramasamy et  al. (2010) isolated 348 endophytes from 24 Malaysian
medicinal plants from the Kuala Pilah Rain Forest, Negeri Sembilan, Malaysia. Two
selected endophytes, Aspergillus sp. HAB10R12 and HAB21F25, were isolated
from roots of Garcinia scortechinii and fruits of Smilax myosotiflora, respectively.
The isolates showed potent anticancer activity against MCF-7 (breast cancer) and
HCT116 (human colon carcinoma) cell lines. Both isolates were from medicinal
plants with ethnobotanical properties. Garcinia scortechinii is widely used by
Malaysians for the postpartum care and the prevention of peptic ulcer. Smilax myo-
sotiflora, also known as “carrion flowers,” is a medicinal herb for treatment of syph-
ilis (Lin 2005). Hamiyah et al. (2012) further investigated the antiproliferative effect
of extracts from Aspergillus sp. (HAB10R12) against four different cancer cell lines
using MCF-7 (breast cancer), HCT116 (human colon carcinoma), A549 (human
Caucasian lung carcinoma), and HepG2 (human Caucasian hepatocyte carcinoma)
using MTT assay. It was reported that the extract was most effective against HepG2,
followed by MCF-7, HCT 116, and A549, cancer cell lines for liver cancer, breast
cancer, colon cancer, and lung cancer, respectively. The cytotoxic effects of the
extracts were linked to the phenolic compounds. However, it needs a further charac-
terization. Hazalin et  al. (2012) further explored isolates KK9L2, KK14L1,
KK21FL2, and KK30RJ2 from various medicinal plants by Hazalin et al. (2009)
and Ramasamy et al. (2010). KK9L2 was isolated from the leaves of Phyllagathis
rotundifolia “tapak sulaiman” used commonly in the postpartum therapy and as a
contraceptive herbal formulation. KK14L1 was isolated from Ampelocissus cinna-
momea Planch, a climber plant used to treat sinusitis, asthma, and hemorrhoids.
KK21FL2 and KK30RH2 were isolated from Zingiberaceae sp. (ginger plant), used
traditionally for the treatment of diarrhea, sea sickness, migraine, and rheumatism.
The extracts of these four endophytes induce apoptosis against the human chronic
myelogenous leukemia cancer cell lines HCT116, MCF-7, and K562. Cytotoxic
effects have been attributed to the six bioactive compounds identified from the
extracts: cytochalasin J, dechlorogriseofulvin, dimethyl-harzianic acid, griseoful-
vin, harzianic acid, and 2-hexylidene-3-methyl-succinic acid.
Endophytes from another common Malaysian medicinal plant, Strobilanthes
crispus, known as “pokok pecah kaca” or “pokok pecah beling” also produced
effective anticancer compounds (Jinfeng et  al. 2017). Traditionally, Strobilanthes
322 L.-S. Yap et al.

crispus is used to treat diabetes, hypertension, and cancer (Koay et al. 2013). In the
study by Jinfeng et al. (2017), two endophytic isolates, identified as Sordariomycetes
sp. (PDA)BL3 and (PDA)BL5, were effective toward five different cancer cell lines:
the human prostatic, alveolar, colorectal, breast adenocarcinoma, and human hepa-
tocellular carcinoma cells. Gas chromatography-mass spectrometry (GC-MS) indi-
cated that the anticancer activity might be credited to the bioactive compounds
pyrrolo[1,2-a]pyrazine-1,4-dione and hexahydro-3-(2-methylpropyl), which are
found primarily in the crude extract. These compounds, however, may demonstrate
different levels of activities depending on the interaction with other compounds
produced by the respective isolates. This phenomenon was observed in a recent
report by Jinfeng et al. (2017). It was found that pyrrolo[1,2-a]pyrazine-1,4-dione
and hexahydro-3-(2-methylpropyl) in extracts produced by (PDA)BL5 were more
efficient in anticancer activity, while the same extract produced by (PDA)BL3 has
stronger antimicrobial activity (Jinfeng et  al. 2017). Beneficial endophytes have
also been discovered from the cinnamon plant Cinnamomum sp. (also known as
“kayu manis padang”). This plant is sourced mainly as a common spice used in
cooking but has also been used traditionally to treat cold and bronchitis and for vari-
ous antimicrobial, antifungal, and antiseptic uses. Several species of endophytes
have been isolated from this plant. Santiago et al. (2012) reported the production of
the anticancer compound from the endophyte Phoma sp., isolated from the plant C.
mollissimum. The anticancer compound was identified as 5-hydroxyramulosin, a
polyketide produced via the action of pentaketide synthase. The production of the
polyketide is from the synthesis of melanin, a metabolic precursor, which increases
the potential of virulence in fungal endophytes and to improve its survivability
under stressful condition. The result showed that the extracted 5-hydroxyramulosin
demonstrated the significant inhibitory effect on the P388 murine leukemia cells.
Other endophytic species such as Colletotrichum gloeosporioides are also found in
Cinnamomum trees such as Cinnamomum malabatrum. This isolate has shown
cytotoxic activity against HeLa (human cervix carcinoma), MCF-7 (human breast
adenocarcinoma), and MG63 (human bone osteosarcoma) cancer cell lines. The
major metabolites extracted from this endophyte are phenol 3,5-dimethoxy acetate
and 4′-isopropylidene-bis-(2-cyclohexyl) phenol.

10.4 Malaysian Marine Plants as Source of Endophytic Fungi

Other than terrestrial medicinal plants, studies have also been carried out on endo-
phytic fungi from marine plants, although the medicinal values of marine plants are
less understood. Ariffin et al. (2011) isolated 64 endophytic fungi from two marine
trees (Pandanus amaryllifolius and Nypa frutican) and six different types of sea-
weeds (Turbinaria conoides, Caulerpa lentillifera, Caulerpa racemosa, Padina
australis, Caulerpa racemosa var., Sargassum polycystum) from Port Dickson,
Negeri Sembilan, Malaysia. The methanolic extracts of the isolates were tested
against seven cancer cell lines: M059J (human brain malignant glioma), DLD-1
(human colorectal adenocarcinoma), NCI-H1299 (human lung carcinoma),
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 323

MDAMB231 (human breast adenocarcinoma), PC12 (rat adrenal pheochromocy-

toma), PC3 (human prostate adenocarcinoma), and B16-F10 (mouse skin mela-
noma). Eight of the most potent extracts with strong cytotoxic activity were reported
to be less cytotoxic to the normal cell line D551 as compared to vincristine and
5-flurouracil, the common drugs used in chemotherapy. This suggested that the
extracts from the marine endophytic fungi were selective toward cancer cell lines
but has less effect on normal cells, which is the main criterion in developing safe
and effective anticancer drugs. Ariffin et al. (2014) made similar observations with
extracts from endophyte S2 from the marine seaweed Turbinaria conoides. In the
in vivo test using 12 healthy rats, no mortality or observable adverse effects was
shown in the rats suggesting no toxic effects of the extracts. Instead, an increase in
the total white blood cell count and hemoglobin levels in the rats was observed.
These studies suggested that the marine endophytic fungi are potential sources of
bioactive compounds with insignificant toxicity in vivo.

10.5 B
 iosourcing for Endophytes Producing Anticancer
Compounds

The process of biosourcing of endophytes and their anticancer compounds begins

with the plant selection. Plants that are selected for isolation of endophytes are usu-
ally from unique environments, have extraordinary strategies for survival, are
endemic and having usual longevity, or have an ethnobotanical history (Strobel
et al. 2004). Most of the endophytes from Malaysian medicinal plants mentioned
earlier are isolated based on the methods proposed by Strobel et al. (2004), Hazalin
et al. (2009, 2012), Ramasamy et al. (2010), Ariffin et al. (2014), and Ting (2014),
with minor modifications. A standard protocol for endophyte isolation consists of
the following steps: surface sterilization of plant materials using 70% of ethanol,
removal of the outer tissues of the plants, excision of the inner tissue, and plating on
the agar plates to allow the growth of endophytes. Hallmann et al. (2006) suggested
the combinations of sterilizing agents to enhance the effectiveness of surface steril-
ization process. Pure cultures are subsequently established and mass cultured to
obtain bioactive compounds for assays. The effects of the endophyte total crude
extract on the viability of different cancer cell lines are evaluated using MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. This assay
is a popular method used in preliminary screening of anticancer activities of a large
number of samples.
For extracts with bioactivities, further investigation on the mode of action is
performed. For example, cancer cell death caused by the apoptosis process can be
studied using the “Cell Death Detection” ELISA assay. This assay applies quantita-
tive sandwich-enzyme-immunoassay principle using mouse monoclonal antibodies
to measure the level of protein markers for apoptosis (Hazalin et  al. 2012). The
crude extracts showing significant cytotoxicity toward cancer cells are further frac-
tionated, and the aliquots of the extracts are analyzed using high-performance liquid
chromatography (HPLC). The aliquots or selected fractions are then tested against
324 L.-S. Yap et al.

different cancer cell lines, and a dereplication technique is used to examine the peak
which exhibits high cytotoxic activity. The dereplication technique of bioactive
compound works by comparing the relevance of HPLC-UV data collected from the
significant peak from the discovered bioactive compound and the data in the in-­
house HPLC-UV library database from known fungal and bacterial metabolites.
Further identification of compounds will only be carried out if there is no match in
the data, thereby indicating that an unknown compound has been found. Identification
of compounds, especially unknown compounds, can be carried out by using nuclear
magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) to elucidate
the structure of the bioactive compound. Novel compounds discovered warrants
further investigation for its potential to be developed as the anticancer agents.

10.6 M
 alaysian Medicinal Plants: Potential Hosts
for Endophytes Producing Anticancer Compounds

It is evident that endophytes from medicinal plants are potential source of antican-
cer agents. Nevertheless, the number of medicinal plants investigated to date is far
from the many that exist in the tropics. There are many more medicinal plants,
which have not been studied extensively. Thus there is tremendous potential for
further exploration and development of the endophytes from these plants. Almost
10% of the 15,000 species of angiosperms in Malaysia show medicinal properties,
reflecting a largely untapped source of endophytes producing valuable bioactive
compounds (Batugal et al. 2004). Malaysia is also strategically located as the point
of flora diversity, where continental Asiatic flora meets and intermingles in Malay
Peninsula that give rise to a greater diversity of plant species (Rao 2010). Typically,
the identification of plant species as a medicinal plant is based on the ethnobotanical
knowledge of the species. Also, this grouping of medicinal plants is motivated by
the knowledge and cultural use by various ethnic groups, ritual practice, location,
and availability. Table 10.4 summarizes the common medicinal plants used for can-
cer treatments in Malaysia. These plants are well known for medicinal properties,
but studies on their endophytes have not been fully understood. Therefore, there is
a vast potential in developing anticancer agents if endophytes from these plants are
isolated. The following section further discusses some of the important medicinal
plants in Malaysia, their valuable compounds, and the prospect or potential of isola-
tion of endophytes from these plants.
Andrographis paniculata, also known as “King of Bitter” or “hempedu bumi,” is
a plant of the Acanthaceae family, which has origin in India and Sri Lanka.
Andrographis paniculata is an annual plant found in moist and shady places and can
grow up to 30–110 cm. It is a medicinal plant well known in Asia for its therapeutic
benefits such as boosting the immune system, treating infections in upper respira-
tory tract and gastrointestinal tract, and treating wounds, ulcers, fever, common
cold, and hypertension (Wasman et al. 2011). Studies have established that major
bioactive compounds of A. paniculata include andrographolide, neoandrogra-
pholide, and deoxyandrographolide, which are antimicrobial, antioxidant,
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 325

Table 10.4  A summary of Malaysian anticancer plants characterized based on their ethnobotani-
cal use
Local Isolated Responsive cancer
Scientific name name phytochemicals cell lines References
Andrographis Hempedu Diterpenoid HeLa, HepG2, Kumar et al.
paniculata bumi lactones A549 (2004)
Zhou et al.
(2010)
Eurycoma longifolia Tongkat ali Alkaloids, HepG2, MCF-7, Kuo et al.
quassinoids, and A549, Kb (2003)
diterpenoids Bhat and
Karim (2010)
Tee and
Azimahtol
(2005)
Goniothalamus Kenerak Styryl lactones, Colon, breast, Abdel-Wahab
umbrosus acetogenins pancreas, kidney et al. (2009)
Breast cancer cells Ghazali et al.
(MCF-7) (2016)
Myrmecodia Sarang Terpenoids, Ovarian cell Hasanuddin
pendans semut phenolics, (SKO-3) et al. (2015)
flavonoids Oral carcinoma KB Yuletnawati
cells et al. (2016)
Human cervix cell Soeksmanto
(HeLa) et al. (2010)
Strobilanthes Pokok – T-47D Yaacob et al.
crispus pecah kaca (2010)
MDA-MB-321 Muslim et al.
(2010)
MCF-7 Bakar et al.
(2006)
Phyllanthus niruri Dukung Terpenes Liver tumor cell Mills et al.
anak (1995)
Mice skin cancer Sharma et al.
(2009)
Typhonium Keladi Linoleic acid, Leukemia WEHI-3 Mohan et al.
flagelliforme tikus hexadecanoic cells, (2010)
acid, Human Mohan et al.
pheophorbide T4-lymphoblastoid (2011)
compounds cell line (CEMss)
Lung and breast Lai et al. (2010)
cancer
“–” Information not found

antidiabetic, anticancer, and immunostimulatory (Rajagopal et  al. 2003; Kumar

et al. 2004; Chakraborty et al. 2011; Das and Srivastav 2014). Andropholides have
strong cytotoxic activities as these are capable of inducing cell cycle arrest at G0/G1
phase through the induction of inhibitory protein p27, thus decreasing the expres-
sion of cyclin-dependent kinase (CDK4) (Rajagopal et al. 2003). Andropholides are
326 L.-S. Yap et al.

also able to initiate cell death signaling by activating the pro-apoptotic Bcl-2 pro-
teins (Bid and Bax) from caspase 8 to mitochondria, resulting in apoptotic cell death
(Zhou et al. 2006). Andropholides enhance chemosensitivity of cancer cells to the
chemotherapy drug doxorubicin by suppressing the JAK-STAT3 pathway (Zhou
et al. 2010). In natural forms, andropholides are diterpenoid lactones, which are the
most prominent chemical constituent in Andrographis paniculata. It is a colorless
crystal with a bitter taste, which was first isolated by Gorter back in 1911. To date,
andropholides have demonstrated activity against an array of cancer cells: human
cervical cancer cells, human hepatoma cells, human breast cancer cells, human
alveolar cell carcinoma, human prostate cancer cells, human non-small cell lung
cancer, human colon cancer, and human promyelocytic leukemia cells (Kumar et al.
2004; Zhou et al. 2006; Geethangili et al. 2008; Lee et al. 2010). In recent years, the
chemical structures of andropholides have been modified to generate analogues and
derivatives such as 14-acetlandrographolide and 3,19-­isoproprylideneandrographol
ide, which exhibit greater anticancer activity and selectivity against leukemia and
colon cancer cells (Jada et al. 2007). As such, the endophytes from A. paniculata
may have untapped potential to produce compounds that are similar in structure and
bioactivity, to the andropholides. Endophytic bacteria found in Andrographis panic-
ulata and Bacillus sp. were reported to show antimicrobial, plant growth-­promoting,
enzymatic, biodegrading, and biosurfactant properties, but the anticancer properties
of the endophytes are yet to be discovered (Arunachalam and Gayathri 2010).
Eurycoma longifolia is also another well-known Malaysian medicinal plant. This
plant is fondly known as “tongkat ali” or “Malaysian ginseng” in Malaysia due to
the presence of long twisted roots. Eurycoma longifolia is a tall tree shrub belong-
ing to the family of Simaroubaceae. The root extracts are primarily used to improve
sexual performance and virility and to treat erectile dysfunction (Nasir et al. 2015).
Secondary use of extracts from E. longifolia includes traditional treatment for fever,
dysentery, and diarrhea, to reduce blood pressure and to help in the postpartum
recovery. In recent years, E. longifolia have been found to have anticancer proper-
ties as well, with bioactivity toward several cancer cell lines such as A549 (human
lung carcinoma), MCF-7 (human breast adenocarcinoma), Kb (human oral epider-
mal carcinoma), and Kb-V1 (human cervix carcinoma) (Kardono et al. 1990; Kuo
et al. 2003). The isolated compounds are mainly β-carboline alkaloids, quassinoids,
canthin-6-one alkaloids, biphenylneolignans, and squalene derivatives (Kardono
et  al. 1990; Tee and Azimahtol 2005; Bhat and Karim 2010). Tee et  al. (2007)
reported that the active fraction (F16) derived from E. longifolia was able to induce
apoptosis in MCF-7 cells by reducing the production of Bcl-2 protein, leading to the
specific proteolytic cleavage of polymerase, deterring the formation of DNA thus
causing cell death in a cancerous cell. Study on endophytes from this plant is limited
to Radu and Kqueen (2002) who discovered endophyte (b53L) with significant anti-
tumor activities in the UCS and UCK bioassay. Wiyakrutta et al. (2004) also reported
a number of endophyte isolates found in E. longifolia in Thailand, which showed
cytotoxicity against KB and BC-1 (breast cancer) cell lines. However, only prelimi-
nary screening was carried out in both these studies, needing further validation of
the effectiveness of the anticancer compounds produced.
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 327

Goniothalamus umbrosus, also known as “kenerak” or “sekulai putih,” is

another important medicinal plant in Malaysia. The plant is a member of the fam-
ily Annonaceae and is easily recognized by its aromatic bark and fusiform leath-
ery flowers. In the early days, the traditional use of roots of G. umbrosus has been
primarily to induce abortion and for postpartum healthcare (Tantithanaporn et al.
2011). In recent years, the bioactive compounds (styryl lactones, acetogenins)
were discovered to show significant cytotoxic activity toward cancerous cells
(Ghazali et  al. 2016). Abdel-Wahab et  al. (2009) reported that ethyl acetate
extracts of G. umbrosus induced cell death in MCF-7 breast cancer cells. In these
cells, membrane blebs appear as a result of cytoskeleton break up from the plasma
membrane, forming apoptotic bodies, and in addition to DNA condensation and
fragmentation, resulting in apoptosis. Both styryl lactones and acetogenins were
reported to exhibit anticancer, anti-inflammatory, antimalarial, immunosuppres-
sive, and antioxidant properties (Ghazali et al. 2016). Examples of styryl lactones
extracted from Goniothalamus sp. are goniothalamin, altholactone, and cardiopet-
alolactone. Goniothalamin activates apoptosis by causing a loss in mitochondrial
transmembrane, resulting in the release of mitochondrial cytochrome C, therefore
activating the caspases enzymatic cascades (Wiart 2007). Altholactone disrupts
the mitochondrial respiratory and causes oxidative stress to the promyelocytic
leukemia cells, leading to apoptosis of the leukemia cells (Wiart 2007). Lee et al.
(2003) reported the styrylpyrone derivative extract (SPD) from Goniothalamus
sp. significantly induced apoptosis in MCF-7 by modulating the levels of Bax
protein, which is correlated with the level of apoptosis. It will therefore be inter-
esting to isolate endophytes from this plant, which has an array of anticancer
compounds. Hsieh et  al. (2009) reported the discovery of two different endo-
phytes, Achromobacter xylosoxidans ss denitrificans (Gs-01) and Curtobacterium
citreum (Gr-01), from Goniothalamus amuyon in Taiwan which showed signifi-
cant cytotoxicity toward HepG2 (human liver hepatocellular carcinoma), Hep3B
(human hepatoma), A549 (human lung carcinoma), MCF7 (human breast adeno-
carcinoma), and MDA-MB-­231(human breast adenocarcinoma) cell lines. Studies
have yet to be carried out on isolating more potential anticancer agent producing
endophytes from G. umbrosus.
Another interesting Malaysian medicinal plant is Myrmecodia pendans, or also
known as the “ant plant” or “ant nest plant” or “sarang semut.” It is named as such
because it has domatia or nesting cavities which are specialized adapted hollow
structures to host ant colonies in it (Hertiani et al. 2010; Engida et al. 2013). This
plant originates from Papua Island from Eastern Indonesia and is commonly found
as an epiphyte on tree branches and trunks of larger trees such as “cajuput”
(Melaleuca), “cemara gunung” (Casuarina), and “kaha” (Castanopsis) (Hertiani
et al. 2010). M. pendans is a myrmecophyte, plant which is associated with ant colo-
nies and is a member of the family Rubiaceae. Among the Myrmecodia genus, only
M. pendans and M. tuberosa exhibit medicinal properties (Hasanuddin et al. 2015).
Their ethnobotanical uses include treatment for cold, nausea, burn, ascaris, hemor-
rhoids, and even cancer. Consumption is by boiling the dried cut tubers in water or
as mixtures with tea or as a mixture with porridge (Hertiani et al. 2010; Yuletnawati
328 L.-S. Yap et al.

et al. 2016). M. pendans has been reported to be a potential anticancer agent due to
its apoptotic and immunomodulatory effects. The presence of terpenoids, phenolics,
and flavonoids were reported to be significantly cytotoxic against cancer cells, such
as the ovarian cancer cell line SKO-3 in in vitro assays (Hasanuddin et al. 2015). In
addition, ethanol extracts of M. pendans also showed significant antitumor activity
in oral carcinoma KB cells (Yuletnawati et al. 2016). The antitumor activity of M.
pendans was also evident against HeLa (human cervix epitheloid carcinoma) and
MCM-B2 (canine mammary carcinoma) cell lines, despite the use of only water
extract (Soeksmanto et al. 2010). Tarman (2015) discovered the antimicrobial prop-
erties of endophytic fungi (R53 and RS6B) isolated from Hydnophytum formi-
carum, epiphytic myrmecophytes found in Indonesia. Thus, the potential of
endophytes isolated from M. pendans to develop anticancer agents is yet to be
explored.
Strobilanthes crispus, also known as “pokok pecah kaca,” “pokok pecah beling,”
or “jin batu” in Malaysia, is a shrub belonging to the Acanthaceae family. This plant
originated in Madagascar then spread to Indonesia. The leaves of S. crispus is boiled
in water and then consumed for the traditional treatment of cancer, diabetes, and
blood pressure (Ghazali et al. 2016). The crude extract of S. crispus has significant
cytotoxic effect against the human breast cancer cell lines. Further subfractions of
the dichloromethane extracts from S. crispus showed higher cytotoxicity toward
breast and prostate cancer cell lines compared to common chemotherapy drugs such
as tamoxifen, paclitaxel, doxorubicin, and docetaxel (Yaacob et  al. 2010).
Nevertheless, in some cases, the subfractions of S. crispus extracts were synergistic
with tamoxifen against MCF-7 and MDA-MB-231 human breast cancer cell lines.
Apoptosis was induced by tamoxifen and further promoted by the subfraction
extracts, leading to the activation of caspase-8 and caspase-9 intrinsic and extrinsic
signaling pathways which led to apoptosis (Yaacob et  al. 2010). Muslim et  al.
(2010) reported that the methanolic extracts of S. crispus were equally effective
toward the human breast ductal carcinoma (T-47D) and breast carcinoma cells
(MCF-7). The potency of the extract was somewhat diluted when administered in
the form of tea. When consumed as tea, the cytotoxicity was only effective against
hormone-dependent breast cancer cell lines (MCF-7) but ineffective against non-
hormone dependent breast cancer cell lines (MDA-MB-231) (Bakar et al. 2006).
This suggested that the effectiveness of medicinal plants for treatment purposes
may be linked to the method of administration. Endophytes isolated from S. crispus
with potential anticancer activity were mentioned in the earlier section of the chap-
ter. Further studies can focus on discovering more endophytes from S. crispus with
stronger cytotoxic activity.
Phyllanthus niruri also known as “gale of the wind” or “dukung anak” in
Malaysia is a tropical herb from the family Phyllanthaceae. This plant has pale
green flowers and tiny fruits. It is used traditionally by the Indian community to
treat stomach, liver, kidney, and spleen diseases (jaundice). It has also been used in
the traditional Chinese medicine (TCM) to treat gallstones and kidney stones. The
extracts from P. niruri were reported to have antiviral properties (against hepatitis
B), anti-inflammatory, antibacterial, antidiabetic, anticancer, and antihepatotoxic
10  Endophytes from Malaysian Medicinal Plants as Sources for Discovering… 329

activities (Bagalkotkar et al. 2006). The anticancer properties of Phyllanthus niruri

are attributed to the terpenes (limonene) found in the plants. Limonene, or monoter-
penes d-limonene, with the aid of perillyl alcohol, activates apoptosis in the tumor
cells and inhibits the growth of tumor cells (Mills et al. 1995; Nasir et al. 2015). In
a study using mice models, Sharma et al. (2009) discovered that the oral administra-
tion of the P. niruri extract reduced the incidence, yield, and burden of papilloma
tumors in mice. Tang et al. (2014) also discovered that the anticancer properties of
Phyllanthus sp. were credited to the ability of the plant extracts to disrupt various
survival signaling pathways, such as MAPKs, P13K/Akt, and NFkB, and to inter-
fere with the regulation of protein involved in the cellular function of tumors such
as glycolysis, apoptosis, and metastasis. Kandasamy et al. (2015) reported the anti-
oxidant and antibacterial properties of endophytic fungi isolated from Phyllanthus
amarus. However, there is still room for further investigations on the anticancer
properties of endophytes from Phyllanthus sp.
Another medicinal plant valued for its tubers is Typhonium flagelliforme, from
the family Araceae. This plant is also known as the “rodent tuber” or “keladi tikus”
and has long been used for various cancer treatments. Traditionally, the plant extract
is obtained by crushing the plants and consuming the extract/juice (Ghazali et al.
2016). In a mice model, Mohan et  al. (2010) tested the dichloromethane tuber
extracts of T. flagelliforme and found that apoptogenic effects were achieved on the
leukemia WEHI-3 cells in the in vitro and in vivo assays. Oral administration of
dichloromethane tuber extracts significantly reduced the number of immature gran-
ulocytes and monocytes in peripheral blood of leukemia mice via the induction of
apoptosis. Mohan et al. (2011) also tested the effect of one of the specific fraction
(F7) on the human T4-lymphoblastoid cell line (CEMss), with encouraging results
demonstrating significant cytotoxicity toward CEMss and selectivity toward non-
cancerous human primary blood lymphocytes (PBLs). The F7 fraction containing
linoleic acid, hexadecanoic acid, and 9-hexadecanoic acid reportedly caused chro-
matin condensation, cell shrinkage, membrane blebbing, the formation of apoptotic
bodies, and cytoplasmic extrusions, leading to cell death. In a separate study, Lai
et al. (2010) reported the antiproliferative activity of a specific fraction (D/F19) of
T. flagelliforme toward lung and breast cancer cells. This fraction has high activity
due to the discovery of four pheophorbide-related compounds, which are antiprolif-
erative. On the contrary, Choo et al. (2001) reported that the hexane extract of T.
flagelliforme demonstrated weak cytotoxicity against murine leukemia cells P388.
These observations from the various reports suggest that the solvents used for the
extraction of the bioactive compounds may be important factors for consideration.
The endophytes from this plant demonstrated antimicrobial and antioxidant proper-
ties (Saraswaty et al. 2013; Ling et al. 2014), but the anticancer activity from the
endophytes is yet to be explored.
The Malaysian medicinal plants are therefore excellent reservoirs to isolate
endophytes that possess anticancer activities. Medicinal plants with anticancer
activities are favored for further studies with the aim to obtain endophytes capable
of producing anticancer compounds similar to its respective host plants.
330 L.-S. Yap et al.

10.7 Conclusions and Future Prospects

Medicinal plants produce valuable secondary metabolites with potential as antican-

cer properties, with some of these products developed as clinical drugs. However,
there are limitations in relying on plants as a sole source of anticancer agents as
discussed earlier in the chapter. Production of anticancer compounds derived from
endophytes is an alternative renewable source, more sustainable. Endophytes in
medicinal plants have been shown to produce novel compounds or compounds simi-
lar to their host plants. These compounds have been studied and documented,
although not extensively investigated. Therefore, there is an enormous potential to
explore more endophytes from the diverse species of medicinal plants in Malaysia.
Concerted research endeavors in this area will lead to the discovery of more antican-
cer agents.

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