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DT:- 20.10.2020
ABSTRACT:-
Breast Cancer is a devastating disease that has claimed many lives and has become the
second most deadliest cancer worldwide. Several studies have found that natural bioactive
compounds produced as secondary metabolites from plant endophytes can enhance the
efficacy of chemotherapy, and in some cases improve some of the side-effects of drugs used
as chemotherapeutic agents. Most cytotoxic drugs act on both cancerous and healthy cells and
therefore elicit side effects such as hair loss, bone marrow suppression, drug resistance,
gastrointestinal lesions, neurologic dysfunction, and cardiac toxicity. Consequently,
development of new anticancer agents with higher efficacy, selectivity, and little or no side
effects is an urgent goal. Among the various endophytic microbes, fungi have been found
most potential microorganisms which are a reservoir of largely untapped bioactive
metabolites. In this review paper we have collected information about some essential
bioactive compounds that has been discovered so far from four different host plants and
discussed their mode of action and efficacy towards the genes causing breast tumors and how
these acts to supress the overgrowing cancerous cells.This paper also contains the comparison
between the commercially available synthetic drugs and environmentally derived bioactive
compounds thus by concluding which has greater efficacy towards uncontrolled growth of cells
.
INTRODUCTION:-
Natural products, especially phytochemicals, have been used to help mankind sustain health
since the evolution of medicine. Phytotherapy (also called herbalism or herbal medicine) has
provided treatment for diseases, including cancer, to the present day . Dietary phytochemicals
have many built-in advantages over synthetic compounds due to their proven safety, low
cost, and oral bio-availability. However, it is only recently that researchers have begun to
elucidate the mode of action of plant-derived agents at the molecular, cellular, and tissue
level. Many natural products are now being researched, and many number of
compounds have shown anticancer and other beneficial actions in modern controlled
studies. Most anti-cancerous natural products interfere with the initiation, development, and
f
proliferation ocancer by modifying various mechanisms including cellular proliferation,
differentiation, cell necrosis, angiogenesis, and metastasis.
The frequency of cancer-related deaths are increasing in developing countries like INDIA at
an alarming rate. Therefore, many research groups have been actively involved in the
development of novel anticancer drugs across the globe. Scientists have begun to
understand and grasp that plants may be reservoirs for an limitless number of
microorganisms, commonly referred as endophytes. Endophytes inhabit at internal plant
tissue in a symbiotic association and can spend most of their life cycle within the
particular host plants. Approximately 2 millions endophytic species are present in the plant
kingdom. It is noteworthy to mention that, a small number of endophytic fungi were
reported to produce plant growth stimulating hormones such as gibberellic acid
and indole acetic acid. Metabolites produced by endophytes can be influenced by the
phytochemicals of their host plants. During the period of co-evolution, some of the
endophytes have developed the ability to produce biologically active compounds that are
similar or identical to their host plants.
Several studies have indicated the possible likelihood of medicinal plants that host
endophytic fungi capable of producing pharmacologically important natural products. It is
reasonable to postulate that the medicinal properties of these plants could be due to the
endophytes residing within them. This has led to an investigation of beneficial compounds
related to plant-endophyte interactions. The interaction between plants and endophytes is
regulated by genes of both the organisms and controlled by the environmental factors . In
other words, the endophyte may encounter metabolically unfavourable condition due to host
defense chemicals . The plant and endophyte association may also change the production
of secondary metabolites in the host plant. The secondary metabolites isolated from
endophytes displayed a broad spectrum of pharmacological properties including anticancer,
antiviral, antibacterial, and antifungal activity. In the subsequent sections, we discuss about
the anticancer compounds extracted from endophytic fungus from diverse habitats that could
be a potential replacement of synthetic drugs currently in use for treating breast cancer.
Catharanthus roseus produces several anti-cancerous alkaloids called as Vinca alkaloids. They are
of several types such as vincristine, vindesine, vinorelbine, vinblastin and vinflunine. This plant is a
host to a plenty of endophytic fungi. C. roseus is a source of about 150 active alkaloids. Vinca
alkaloids vincristine and vinblastine are used in the process of chemotherapy with vincristine are
for the treatment of Breast cancer. They are also being used for acute leukemia, Hodgkin and non-
Hodgkin lymphomas. Vinblastine is greatly used as the major component in chemotherapy for
germ cell, ovarian, bladder and several types of brain malignancies.
Vinorelbine alone or in combination with 5-FU is an effective treatment for pre-treated advanced or
metastatic breast cancer patients. The combination of vinorelbine with 5-FU is quite more efficient
than vinorelbine alone.
Combination chemotherapy containing vinorelbine and doxorubicin has been a great treatment of
advanced breast cancer with response rates ranging from 57 to 74% as first-line therapy.
It causes the arrest of the metaphase and specifically of the microtubules that also includes the
mitotic spindle apparatus.
Vinca alkaloids and anti-microtubule agents also affects on both the non-malignant and malignant
cells in the non-mitotic cell cycle, as the microtubules are involved in many non-mitotic functions.
Binding of the vinca alkaloids to these sites interrupts microtubule congregation.
One of the most important effect of low drug concentrations is decreasing the rates of both growth
and shortening at the assembly end of the microtubule. This produces a kinetic cap and suppresses
its function.
The disturbing effects of the vinca alkaloids on microtubule dynamics is that, it causes metaphase
arrest, particularly at the ends of the mitotic spindle.
Mode of Mechanism: -
The drug- Podophyllotoxin first destabilizes the microtubules by binding tubulin, thus preventing cell
division. Sometimes some of its derivatives appears as binding activity to the enzyme topoisomerase II
(Topo II) during the late S and early G2 stage of cell cycle.
Once this process is over, the etoposide binds and stabilizes the temporary DNA break which was caused by
the enzyme and disrupts the reparation of the break through from the double-stranded DNA passes, and
hence, consequently stops DNA unwinding and replication.
Mutants are resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as
etoposide (VP-16), this process is described in chinese hamster cells. This Mutant Chinese hamster cells
resistant to podophyllotoxin are mainly affected in a protein P1 region that was later identified as the
mammalian HSP60 or chaperonin protein.
Further, the podophyllotoxin is classified as an arytetralin lignan because it has a ability to bind and
deactivate DNA. Itself and its derivates bind to Topo II and prevent its ability to catalyze the rejoining of
DNA that was broken for replication.
At last, experimental evidences have shown that these arytetralin lignans can interact with
cellular factors to create chemical DNA adducts, thus further deactivating the dsDNA.
CYTOTOXICITY OF PODOPHYLLOTOXIN:-
In the present study, we investigated whether stabilizing micro- tubules by taxol regulates the
invasiveness of MDA-MB-231 and MDA-MB-468 cells. The mechanism of PTX cytotoxicity
highly depends on the concentration of the drug in the cell as demonstrated in in vitro studies.
Giannakakou et al. [72] documented that the reduction of proliferation of the lung carcinoma
cell line A549 as well as breast MCF-7 cells after treatment by PTX at concentrations above
12 nM resulted in G2/M arrest. Interestingly, lower concentrations of PTX (3–6 nM) exerted
similar potential to suppress the proliferation of cancer cells, resulting in programmed cell
death [72]. A study focusing on drug concentration analyzed the effect of low doses of PTX
(10 nM) on cancer cell invasiveness. In this in vitro study, researchers evaluated the impact of
the non-anti-mitotic concentration of PTX resulting in the reduction of transwell invasion of
MDA-MB-231 as a consequence of the regulation of voltage-dependent sodium channel
expression [73]. Additionally, Biomolecules 2019, 9, 789 6 of 22 the potential role of low
doses of PTX (20 nM) combined with a Wnt signaling inhibitor regulated the molecular
events, including E-cadherin upregulation and β-catenin reduction, leading to suppression of
tumor growth, metastasis, and angiogenesis in BC.
4. SOURSOP :-
Some research work showed that paclitaxel, an important chemotherapy agent for breast
cancer, can directly attack the internal endoplasmic reticulum (ER) calcium store to release
apoptosis—promoting calcium signals depending on dosages . In this study, we focus on the
role of external calcium to fully understand the calcium—regulated mechanisms of
paclitaxel-induced apoptosis .Graviola (Annona muricata) is a small deciduous tropical
evergreen fruit tree, belonging to the Annonaceae family, and is widely grown and
distributed in tropical and subtropical regions around the world. The reported therapeutic
benefits of graviola against various human tumors and disease agents in in vitro culture and
preclinical animal model systems are typically tested for their ability to specifically target the
disease, while exerting little or no effect on normal cell viability. At least ten solvent extracts
in addition to an extract from fungi (Periconia sp.) collected on A. muricata that contains
bioactive compounds (have been tested for their anticancer properties and other health
benefits. Anti-cancer effects of AGEs and extracts are derived from the different parts of A.
muricata.
Annomuricin B
Annomuricin C AGE Leaf Cytotoxic
activity
Breast MCF
cancer 7 Muricatocin C AGE Leaf Cytotoxic
activity
(2,4-cis)-10R
Annomacin A one + AGE Leaf ED50
(2,4-trans)-10R- =5.70*10-1µg/ml
Annomacin A one
The major bioactive components that have been extracted from various A. muricata's parts are
known as annonaceous acetogenins (AGEs). These are derivatives of long-chain (C32 or C34)
fatty acids derived from the polyketide pathway, reviewed in . Many of these derivatives are
reported to be selectively toxic to cancer cells, including multidrug-resistant cancer cell lines .
Annonaceous acetogenins induce cytotoxicity, at least in part, by inhibiting mitochondrial
complex I, which is involved in oxidative phosphorylation and ATP synthesis . As cancer cells
have a higher demand for ATP than the normal cells, mitochondrial complex I inhibitors have
potential in cancer therapy . In breast cancer, cytotoxicity can be induced in MCF-7 cells using
any of the following purified AGEs: annomuricin A, B , C , or E ; muricatocin A, B, or C ;
muricapentocin ; annomutacin ; annohexocin ; annopentocin A, B, or C ; murihexocin A, B , or
C; muricoreacin ; muricatacin [; isoannonacin ]; isoannonacin-10-one ; goniothalamicin ;
gigantetrocin A or B , muricatetrocin A or B , cis-annonacin; cis-annonacin-10-one; cis-
goniothalamicin; arianacin; or javoricin . In addition, synergistic therapeutic effects have been
shown with the combination of AGEs. For example, cytotoxicity in breast cancer) has been
observed using a combination of (2,4-cis)-10R-annonacin-A-one and (2,4-trans)-10R-
Annonacin-A-one, or a mixture of cis-annomuricin-D-one and trans-annomuricin-D-one.
Leaf extracts of A. muricata induce apoptosis in breast MDA-MB-468 cancer cells through
caspase-3 activation . Similarly, A. muricata fruit extract induces apoptosis in breast T47D
cancer cells.
CONCLUSION:-
Natural products have the potential to serve as chemotherapeutic as well as chemopreventive
agents in the treatment of breast cancer. The bioactive compounds derived from many natural
plant sources could be a possible means to provide protection against cancer or used as a
treatment approach against cancer. Palcitaxol and vinca alkaloids show much promise to be
developed as chemopreventive and/or novel therapeutic agents in the fight against cancer as
there are many studies that show that these bioactive agents possess potent anticancer activities.
And among the synthetic drugs Abimaciclib has shown most promising results .But since
naturally derived compounds causes less side effects,we could think of replacing it by the
synthetic one,but since some commercial drugs exhibited high cytotoxicity and less consume
lesser time to induce its action on cancerous cell we also cannot completely abolish it. Hence,
more work needs to be carried out to know to understand exactly how these compounds act as
this information would be useful in developing therapeutic cocktails made up of various
bioactive agents that can target different molecules to produce better therapeutic effects.
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