Apoptosis Caused by Natural Compounds in
Cervical Cancer Cell Line
Deepa, Sweta Pal, Harsh Goel and Abhimanyu Kumar Jha*
Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines & Research, India
Submission: June 24, 2019; Published: July 10, 2019
*Corresponding Address: Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines & Research, Ghaziabad, Uttar Pradesh, India
How to cite this article:Deepa, Sweta P, Harsh G, Abhimanyu K J. Apoptosis Caused by Natural Compounds in Cervical Cancer Cell Line. Cancer Ther
002 Oncol Int J. 2019; 14(2): 555886. DOI:10.19080/CTOIJ.2019.13.555886
Cancer is a life-threatening disease involving out-of-control of cell growth in a mammalian body, these are of many types like (liver cancer, cervical cancer, skin cancer, breast cancer) There are many types of therapies available those are effective against cancer like (chemotherapy, radiotherapy). But these therapies are very painful and also cause some effect on healthy cells. Cervical cancer is one of the leading cancers caused by HPV (human papiloma virus) which mainly occur in women and after the age of 22 year the chance of cervical cancer increase. It is obtained from the cells of cervix. It can be detected through the regular Pap smear. But now days natural compounds are one of the best treatments to fight from the cancer because in natural compound many types of compounds are available those have capability to kill approximately 80% of the cancerous cells. Natural compounds include Quercetin, Eugenol, Green Tea, Genistein etc. which are known to be very effective against cervical cancer.
Keywords: Cervical cancer; Human papilloma virus; Apoptosis; Quercetin; Eugenol
Cancer is a type of disease that spreads due to uncontrolled of cell growth due to the collection of defects or variation in their DNA and with imminence to attack or distribute to other parts of the body. Cancer is specified as a wide group of several infections normally characterized by persistently uncontrolled and unnatural at usual cell yield, where cell proliferation comes via mitotic deregulations and thus contributes to overgrowth of cancerous cells. In the case of malignancy, these cells may transmigrate from one body parts to other in the form of tumors and metastasis in blood stream sand lymphatic system (Ochwang et al., 2015 and Srivatava et al., 2015). Various studies have demonstrated that the cancer danger at the level of particular organs is due to exposure to particular environmental chemicals, biological factors (as Human Papilloma virus, Helicobacter hepticus, HIV1, HBV) or physical factors (such as X-radiation, gamma radiation) (Zulkipli et al., 2015). Research proposes that most malignancies are caused by a dysfunction of multiple genes coding for macromolecules like as growth factors, growth factor receptors, anti-apoptotic proteins, transcription factors, and tumor suppressors, all of which establish the aim for disease treatment (Cogliano et al., 2011 and Vogelstein et al., 2004).
Cervix cancer is one of the numbers of cancer, which are second main origin of cancer deaths in women worldwide. At least 500,000 patients are diseased yearly those are suffering from cervical cancer in the developing world ( North et al., 2007). In 2006 there were generally 9710 new diseases and approximately 3700 deaths in United States (Atlanta et al., 2008). A persevering human papilloma virus (HPV) infection is a requirement for the growth of precursor lesions and invasive cervical carcinoma. Invasive cervical malignancy has a long premalignant phase termed cervical intraepithelial neoplasia (CIN). The preserve development from HPV infection to CIN and invasive disease generate CIN an excellent aspirant for chemo prevention (Alvarez et al., 2003). Cervical carcinoma is a disease that development quite slowly and starts with the precancerous condition called as dysplasia. Dysplasia is readily identified in a regular Pap smear and is absolutely treatable. Cervical carcinoma is a lethal malignancy obtains from the cells of the cervix. Due to programmed cell death, in a day approximately 50 and 70 billion cells lose in average adult human (Mitchell et al., 1995). Infection with the common human papillomavirus (HPV) is a cause of approximately 90% of all cervical carcinoma. About half of the sexually transmitted HPVs are companion with cervical carcinoma.
Many reports have been summarized epidemiologically and experimentally on natural compound and its relation to prevention of cancer (Johnson et al., 2005), especially in relation to tea Compound and its effect on cervical carcinogenesis (Ahn et al., 2003) and Yokoyama et al., 2004). Luteolin, is one of the most
powerful flavonoids, can stop the development of tumor cells
in vitro and in vivo via suppression of tumor cell proliferation,
initiation of cell cycle arrest and apoptosis by inhibiting enzymes
required in cell activation such as phosphodiesterase’s kinases
and DNA topoisomerases. All recent approaches, in relation to
the prognosis of patients and metastatic cervical cancer remains
inadequate (Yang et al., 1998).
Programmed cell Death refers to controlled regulation of
cycle and removal of undesirable cells at right times without inducing
surrounding tissue impairment (Millimouno et al., 2014
and Gerschenson et al., 1992). Programmed cell death occurs
generally during maturation and aging and as a homeostatic
mechanism to keep cell populations in tissues and as a defense
mechanism such as in immune reactions or when cells are damaged
by disease or noxious factor. Programmed cell death is a
form of apoptosis characterized by stereotypic structural changes
executed by cysteine-aspartate proteases (caspases) and regulated
by the Bcl-2 family of proteins (Allen et al., 1993 and Wei
et al., 2001). Numerous reports have described the mechanism
by which p53 induces programmed cell death. As p53 functions
principally as a transcription factor, it is important to explore
the genes regulated by p53 that lead to the regulation of programmed
cell death. Early studies showed that wild type p53 can
bind the bax gene promoter region and regulate bax gene transcription
(Miyashita et al., 1995 ).
Electron and light microscopy have identified the various
structural changes that occur during programmed cell death.
During the early process of programmed cell death, cell shrinkage
and pyknosis is visible by light microscopy (Oltvai et al., 1993).
With cell shrinkage, the cells are smaller in size, the cytoplasm
is thick, and the organelles are more tightly packed. Pyknosis
is the result of chromatin contraction and this is the almost
characteristic feature of programmed cell death. The apoptotic
cell seems as a round or oval mass with dark eosinophilic
cytoplasm and thick purple nuclear chromatin break up.
The mechanisms of programmed cell death are extremely
complicated and sophisticated, requiring an energy-dependent
cascade of molecular events. Research shows that there are two
most important programmed cell death pathways: the extrinsic
or death receptor pathway and the intrinsic or mitochondrial
pathway. Still, this is now demonstrated that the two pathways
are associated and that molecules in one pathway can persuade
the other (Igney et al., 2002). It has been found that granzyme
A-induced apoptosis is a caspase-independent pathway through
single stranded DNA damage. All the three (intrinsic, extrinsic
and granzyme B-induced) pathways of apoptosis arrive together
on the same point putting to cell death by the activation of
caspase-3/7 followed by cell shrinkage, chromatin contraction and fragmentation of chromosomal DNA, degradation of nuclear
as well as cytoskeleton proteins etc.
The extrinsic signaling pathways that begin programmed cell
death include trans membrane receptor-mediated interactions.
These include death receptors that are members of the tumor
necrosis factor (TNF) receptor gene superfamily members of
the TNF receptor family share similar cyteine-rich extracellular
domains and have a living substance domain of concerning
eighty amino acids referred to as the “death domain. This death
domain plays an essential role in transmittal the death signal
from the cell surface to the intracellular signaling pathways. The
best-characterized ligands and corresponding death receptors
involve FasL/FasR, TNF-α /TNFR1, Apo3L/DR3, Apo2L/DR4 and
Following polymer injury, enlarged level of Bax and/or faded
level of Bcl2 could permeabilize the mitochondria to unleash
pro apoptotic factors, like cytochrome c, that trigger resultant
activation of procaspase-9, followed by downstream apoptotic
effectors. Recently it has been found that in response to polymer
injury, activation of caspase-2 is needed before mitochondrial
permeabilization and unleash of cytochrome-c (Guo et al., 2014).
Activation of caspase-2 would possibly occur while not process
of the precursor molecule but, oligomerization is a crucial step
for caspase-2 activation.
Being the global cause of mortality and morbidity, these
cancer diseases need to be dealt and/or treated in an effective
way (Islam et al., 2013). ). Hence, these diseases are being treated
with various approaches (either alone or synergistically) since
long and still are in continuous use. Some of these treatment
regimens include chemotherapies, radiotherapies, immune
therapies and surgeries.
Natural products have long been used as the important
sources of cervical cancer treatment which is estimated to become
the major cause of death in the current century. There are
more than one thousand species that have been found to possess
significant anticancer properties (Mukherjee et al., 2001 ).
Natural compounds are obtained from plants, marine and microorganism’s
life forms have gained a significant interest among
cancer researchers for the potential to influence multiple cancer
hallmarks. Drugs derived from natural products with anti-bacterial,
anti-coagulant, anti-parasitic, immune suppressive and
anticancer activity are capable of treating 87% of categorized
human diseases. Among the 128 anticancer drugs released on
the market between 1981 and 2010 were natural products and
32 were derived from natural products (Mukherjee et al., 2001 ).
The another bioactive phytochemical sulforaphane (SFN),
highly present in broccoli, sprouts, cabbage and kale, has been
broadly studied for its anticancer activity. SFN has been observed
to enhance xenobiotic metabolism and promote cell cycle arrest
and apoptosis in several human cancer cells (Clarke et al.,
2008). Like many other plant polyphenols SFN can also change
epigenetic events in cancer cells. Overall, SFN is an effective tool
to fight from the cancer and safe chemo preventive molecule.
Indole-3-carbinol (I3C) is a hydrolyzed compound of the
phytochemical glucosinolate, existing in cruciferous vegetables,
along with broccoli, cabbage, cauliflower, mustard, and radish.
Conversion of glucosinolate to I3C is catalyzed by an accelerate
gift within these plants known as myrosinase; acidic pH in
the abdomen converts I3C to di indolyl methane (DIM). Each
I3C and DIM are reported to induce programmed cell death in
several neoplastic cell lines from solid tumors of various organs
by poignant variety of kinases and nuclear receptor mediated
signaling (Banerjee et al., 2011). A study with human colon
cancer HT-29, SW620, RKO, LS174T, and HCT-116 cell lines
and in tumor xenografts showed that DIM evoked proteosomal
mediated degradation of class I HDACs (1–3,8) with no impact
on class II HDAC proteins.
Resveratrol is a phytoalex in mainly present in grapes. It
absolutely was shown resveratrol causes programmed cell death
in HL60 cells and T47D breast cancer cells (Wheat et al., 2008
). It induces programmed cell death through CD95 signaling–
dependent programmed cell death in HL60 and T47D cells.
Resveratrol, a polyphenol found in red wine, peanuts, and some
berries, possesses antioxidant and anti-inflammatory properties,
and has been found to possess beneficial effects in cardiovascular
disease and cancer (Savouret et al., 2002 ). Resveratrol exhibits
weak DNMT restrictive activity in MCF7 breast carcinoma
cells and was unable to reverse methylation of various tumor
suppressor genes. Resveratrol activates SIRT1 chemical change
(catalytic) core freelance of its terminal domains, indicating the
existence of a resveratrol binding site at intervals the chemical
change (catalytic) core of the enzyme (Tili et al., 2010). Topical
application of resveratrol to the skin completely decreased
tumorigenesis, still the impact was decreased in SIRT1-null mice,
suggesting resveratrol needs SIRT1encoded super molecule
(protein) for its protection (Wang et al., 2008). Resveratrol has
also been shown to supply protection from cancer by modifying
All over the world most widely consumed beverage is tea
after water it has various styles of consumption like green, black and oolong tea (Yang et al., 1993). Tea polyphenols, namely the
catechins mainly found in green tea, have been observed to reduce
the risk of numerous diseases, including cancer. Epicatechin
(EC), Epicatechin-3-gallate (ECG), Epigallocatechin (EGC),
and Epigallocatechin-3-gallate (EGCG) are four predominant
catechins present in green tea, EGCG constitute over 50% of the
total catechin extracted from green tea and has been broadly
studied for its anticancer effects (Issa et al., 2007 ). The effects
of green tea compounds on cell growth, apoptosis, cell cycle,
and organic phenomenon were examined and characterized
Yokoyama et al. . Each epigallocatechingallate and
polyphenols inhibit immortalized cervical tissue and neoplastic
cell growth (Ahn et al., 2003 ). Cell death induction and cell cycle
changes were determined during a dose-dependent manner.
This study provides information on the potential mechanisms
of action of tea compounds in suppression of HPV-related
cervical cells, and it will change us to assess the feasibleness of
victimization these agent’s (Li et al., 2005 ).
Genistein is a phytosterols belonging to Flavonoids family.
Programmed cell death induction by genistein in human
promyelocytic HL-60 leukaemic cells has been confirmed by
using flow cytometric analysis (Li et al., 2005 ). It inhibits
tyrosine kinase, angiogenesis and arrests cell cycle in G2/M
phase ( Wheat et. al., 2008).
Quercetin (Q), is a flavonoid compound which is occur in
vegetables, fruits, tea and other plant-derived foods. Quercetin
has a unique biological property which is used to improving
mental/physical performance and reducing infection risk (Liu et
al., 2013 & 2003), (Guo et al., 2014 ). Quercetin has been occurred
to have pro-apoptotic and anti-proliferative effects on HeLa
cells (Xiang et al., 2014). Quercetin is active in all the stages of
carcinogenesis from initiation to invasion and metastasis and is
able also to undermine the basis of the growth and maintenance
of tumors. PI3K/Akt pathway in HeLa cells have been found to
mainly mediate the anti-proliferative and apoptotic processes
caused by Quercetin. Quercetin is an antioxidant in vitro because
it can scavenge radicals, inhibit lipid peroxidation and chelate
metals (Rice et al., 1996). Quercetin is also used in the prevention
of cardiovascular disease. However, to induce this health affects
in humans, quercetin must enter the systemic circulation.
Quercetin in foods is bound to sugars, mainly as β-glycosides,
and the bioavailability of these various quercetin glycosides is
affected by their sugar moiety (Hollman et al., 1995).
Eugenol is a natural compound found in many plants like
clove, cinnamon etc. It has been used as an antiseptic agent.
Clove (Syzygiumaromaticum) is a flower bud used as a spice
in foods for enhancing the flavor. The aroma and flavor of the
clove is due to the presence of eugenol (70-85%), annecessary oil. The other two major compounds in the clove extract are
Eugenyl acetate (15%) and β-caryophyllene (5-12%). It is
demonstrated that eugenol is used as analgesics in dental
treatment and is also combined with zinc oxide to be used as
dental fillings (Sonalker et al., 2014 ). They reveal anti-microbial
against many foods borne pathogens. Additionally, it also
exhibits strong anti-fungal property against Candida aspergillus
and dermophyte species (Singh et al., 2016 ). Eugenol together
with 5-fluorouracil exhibited lot of toxicity against the cervical
cancer cells (HeLa). Eugenol has ability in the prevention of
diseases such as cancer, coronary heart, inflammatory disorder,
and neurologic degeneration. It contained phenolic structure
and natural antioxidant such as which plays an important role in
protecting tissues toward free radical damages (Fujisawa et al.,
2002) (Traka et al., 2005 & Mukhtar et al., 1999).
The natural compounds play an important role in cancer
chemoprevention. They can help against cancers like cervical
cancer, through apoptotic as well as other pathways. These
compounds could be tested in clinical trials in cervical cancer
patients. This would further validate the experimental studies
and would translate the research findings from bench to bedside.
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