Cancer a standard life expectancy. There are over

Cancer being a catastrophe of the frame of
higher multicellular organisms consequential from the abnormal growth of the
cells attains modifications in the statement of copious amendments, prompting
dysregulation of the conventional cell programming concerned with the cell
division and cell separation. This upshot in an unevenness of cell replication
and cell passing that stimulates the development of a tumor cell population.
The characters that portray a lopsided growth of a malignant tumor are the
competence to strike locally, to sweep to neighboring lymph nodes, and to
metastasize far off organs in the body. Clinically, growth seems, by all
accounts, to be an extensive assortment of diseases with various phenotypic
attributes. As a cancerous growth ensues, genetic drift in the cell population
forms cell heterogeneity in such features as cell antigenicity, invasiveness,
metastatic potential, rate of cell proliferation, differentiation state, and
response to chemotherapeutic agents. At the molecular level, all cancers have
plentiful things in mutual, which implies that the ultimate biochemical lesions
steering to malignant transformation and progression can be fabricated by a
common but not analogous pattern of alterations of gene readout. In general,
malignant cancers cause noteworthy morbidity and will be lethal to the host if
not treated. Omissions to them give the marks to be concealed, laidback cancers
that may remain clinically undetectable (or in situ), permits the host to have
a standard life expectancy. There are over 100 diverse categories of
cancer, and each is classified by the type of cell that is initially affected,
and these include breast cancer, cervical cancer, skin cancer, leukemia, lung
cancer, prostate cancer, and so on. Chronic degenerative
diseases like cancer have touched rampant proportions and are regarded as a
serious medical condition and therefore, the treatments of these diseases are
of clinical importance (WHO, 2005). In consequence, the medicinal plants play a
pivotal role and are considered as the basis for health preservation and care
worldwide. There have been researches done on the anti-cancerous
properties of plants and recognized for centuries.

 The National Cancer Institute (NCI) has screened approximately
35,000 plant species for conceivable anticancer activities. Among them, about
3,000 plant species have established reproducible anticancer activity. Various
studies have concentrated on the anticarcinogenic properties of plants, to name
a few, Abrus precatorius, Albizza lebbeck
Alstonia scholaries Anacardium occidentale hepatoma, Asparagus racemosa,
Boswellia serrata, Ethyrina suberosa, Euphorbia hirta, Gynandropis pentaphylla,
Nigella sativa, Peaderia foetida, Picrorrhiza kurroa, Withania somnifera, Annona
muricata. Due to the therapeutic ability of the species Annona muricata of the family
Annonaceae, wide range of studies has been made over the last decade. The
bioactivity as well as toxicity of this species has diverted the attention
towards itself.

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1.   
Annona muricata: Description
and ethno-medicinal uses:

Annona muricata, commonly called Soursop or Graviola, is
a tropical plant species renowned for its edible fruit which has selected
restorative benefits, in addition to particular toxicological impacts (23). This plant is a species of the genus Annona, of the
Annonaceae family, order Magnoliales and Division Magnoliophyta. The genus Annona comprises over 70 species among
which A. muricata is the most extensively grown. The
Soursop tree grows up to 5– 10 m tall and 15– 83 cm in breadth with low
branches. It has a tendency to blossom and fruit a large segment of the year,
however there are more characterized seasons relying upon the altitude. It is
scattered in the tropical areas. The
flowers of the plant are showy and are yellow-green colored. The fruit
here is an ovoid berry, dull green in shading. Each fruit may comprise 55–170
black seeds when fresh and they transform to light brown when dry. The flesh is
white and creamy with distinctive aroma and flavor.

                     

               Figure 1: A) Annona muricata, fruit tree    B)
Leaves     C) Fruit, an ovoid berry    D) Flower

 

Traditional medicinal benefits of leaves,
bark, fruit and seed of A. muricata have been
the emphasis of myriad medicinal routines(14, 17). The most
significantly used preparation in traditional medicine is the decoction of
bark, root, seed or leaf and applications are wide-ranging. The ingestion of
leaves decoction is used as analgesic and also it is used to cope with
discomfort accompanying colds, flu and asthma. The use of leaves to treat
malaria is very substantial. The fruit is not only cherished as food, but the
juice is used as galactogogue to treat diarrhea, heart and liver diseases, and
against intestinal parasites. Customary
therapeutic qualities of A. muricata
have been recognized in tropical locales to ponder different afflictions, for
example, fever, torment, respiratory and skin disease, bacterial infections,
hypertension, aggravation, diabetes and
cancer. There have
been a number of reports on the ethno-medical uses of A.
muricata leaves
including treatments for hypertension, diabetes and cancer. Most parts of the A. muricata tree,
similar to that of the other Annona species, namely A.
squamosa and A. reticulata are widely used as
local and habitual medicines contrary to a large number of human inflammations,
infections and disorders. The pulp of the fruit is used as natural medicine for
joint pains, dysentery, neuralgia, diarrhea, rheumatism, fever, malaria, skin
rushes and worms. The fruit is also eaten to increase mother’s milk after
parturition. The leaves are used to control cystitis, body aches and diabetes.
Additionally, the administration of the leaf’s decoction is thought to display
anti-rheumatic and neuralgic effects. In addition, the cooked leaves are
topically used to treat abscesses and rheumatism that was reported by de Sousa OV and colleagues (10).

 The crushed seeds are
thought to have anthelmintic activities antagonistic to external and internal
worms. In tropical Africa, the plant is employed as an astringent pesticide,
and insecticide; along this it is used to treat coughs, pain and skin diseases.
In India, the fruit and flower are used as remedies against catarrh, while the
root-bark and leaves are well known to have an anti phlogistic and anthelmintic
activities which was worked upon
by Adewole SO, Ojewole J (2). In
Malaysia, the crude extract of A. muricata and A.
squamosa is used as a syrup on the head to buffer from fainting. In South America and tropical Africa, including Nigeria, leaves
of A.muricata are implemented as an ethnomedicine opposed to
tumors and cancer. Moreover, the smooth muscle relaxant, hypotensive
hypoglycemic, anti-inflammatory, sedative, and antispasmodic effects accredit
to the leaves, barks and roots of A. muricata. Moreover along
with the ethnomedicinal uses, the fruits are widely employed for the
preparation of beverages, ice creams,and syrups (3, 22, 24, 27) .

 

2.    Phytoconstituents:

Over 200 chemical compounds have been documented and isolated from this
plant; out of which the most prominent compounds are the alkaloids, phenols,
flavonoids and acetogenins. Based on the in vitro studies, extracts and
phytochemicals of A. muricata have been
sorted out as anti-microbial, anti-inflammatory, anti-protozoan, antioxidant,
insecticide, larvicide, and cytotoxic to tumor cells. Researches on
the extracts and isolated compounds of A.
muricata suggested contraceptive, antitumor, anti-ulceric, wound healing,
hepato-protective, anxiolytic, anti-stress, anti-inflammatory, anti-icteric and
hypoglycemic activities. To amplify the hypoglycemic activity of the ethanolic
extracts of A. muricata leaves,
various clinical studies were conducted. 
Cytotoxic, antioxidant, antimicrobial, anti-nociception and hypotensive
activities are analyzed and developed by mechanisms of action of a few
pharmacological activities. Although, some phytochemical compounds isolated
from A. muricata have shown a
neurotoxic effect in vitro and in vivo. Hence, to define the magnitude of the
effects, optimal dosage, long-term safety, and potential side effects,
additional studies on these crude extracts and isolated compounds should be
carried out (33).

Constant examinations on diverse parts of the A. muricata have shown the
occurrence of varieties of phyto constituents and compounds, including
flavonoltriglycosides (FTGs) alkaloids (ALKs), phenolics (PLs), megastigmanes
(MGs), cyclopeptides (CPs) and essential oils. The existence of various
minerals such as Ca, Na, Fe, K, Cu and Mg imply that regular intake of A. muricata fruit can help
furnish essential nutrients to the human body. However, Annona species,
including A. muricata, have been shown to be a vital source of annonaceous
acetogenin compounds (AGEs). Almost all the parts inclusive of the fruits, leaves, stems and roots of
this plant are known to be rich in flavonoids, isoquinoline alkaloids and
annonaceous acetogenins. (24, 26, 27, 29, 38, 44). Long chain (C-32/C34) fatty acids in
the polyketide pathway give rise to Acetogenins, a unique category of C-35/C37
secondary metabolites. It is explained by combining fatty acids with  2-propanol unit at C-2 that gives a
methyl-substituted ?, ?-unsaturated ?-lactone. After 1982,a number of
acetogenins have been identified with the discovery of uvaricin from Uvaria
accuminata  . About 500 have been reported from numerous parts of the
plants in the Annonaceae family. In recent times, AGEs have drawn significant
scientific interest due to the remarkable structures and broad spectrum of
biological activities. The active annonaceous acetogenins have shown to be
successful in inducing death in cancer cells that are resistant to even
chemotherapeutic drugs. It is found that these annonaceous acetogenins aids to
debilitating side effects such as neurotoxicity which results in easy traverse
of the blood-brain barrier and causes a typical Parkinson’s disease. This
inhibits the growth of new drug entities. Various biological activities have
been reported for AGEs, including antimalarial, anti-parasitic and pesticidal
activities. Yet, the toxicity against cancer cells and inhibitions of the
mitochondrial complex I are initially influenced by the physiological activities
of AGEs (11, 12, 25).

4.     Anticancer activity:

There are plentiful reports
that signify anti-proliferative effects of various extracts of the plant and
isolated AGEs against various cancer cell lines. As mentioned earlier cancer is
categorized based on the primary tissue it occurs in. The antitumor effects of A. muricata against various cancer cell
lines are described here.

Breast Adenocarcinoma:

An
oncogene, the epidermal growth factor receptor (EGFR) that is quite often overexpressed
in breast cancer (BC) and is linked with poor prognosis and drug resistance. Studies
have revealed that there is a selective inhibition of breast cancer cells via
EGFR down regulation by the extract of Graviola. Thus, EGFR is a rational
target for BC therapy development. In addition, xenografts mouse model studies experiments
have showed that the fruit extract reduces the growth of BC cells (9). The Fruit extract specifically suppressed the growth of
EGFR-overexpressing human BC (MDA-MB-468) cells but did not in non-tumorigenic
human breast epithelial cells (MCF-10A). These reports bolster the evidence that Graviola
has selective anti-growth effects between cancer and non-cancer cells (37). In a report by Yu-Min Koa and colleagues it was shown
that Graviola favors apoptosis in ER-related pathways. In addition, it was also
noted that Graviola had subsided MCF-7 tumor growth while hindering ER-cyclin
D1 and Bcl-2 protein expressions in nude mice (46). A promising antitumor effect was reported in an in vivo study on 7,12-dimethylbenzene anthracene
(DMBA)-induced cell proliferation in the breast tissues of mice. Oral
administration of the Graviola leaves
supposedly have protective effects towards the development of breast
carcinogenesis was shown by DMBA as it induced a protective effect against DNA
damage.

Cervical Cancer:

In a study by A
N Artanti et,al the results demonstrated that acetogenins from Annona muricata have growth inhibitory
and cytotoxic effect on cervical cancer cell line. The acetogenins from Annona muricata leaves performed potent
cytotoxic effect on HeLa cells. Decreasing cell viability may be because of
either cell death or cell cycle arrest. The mechanism of cell cycle
distribution is also associated with some of celuller protein especially p53 protein.
p53 is a tumor suppressor protein. In this study, it was observed that AGEs
from Annona muricata treatment
increased p53 level in nucleus. Therefore, AGE may be regarded as a viral
inhibitor agent and as competitor of vaccine to prevent the development of
cervical cancer. In conclusion, extracts of Annona
muricata leaves indeed has potential to be developed as a
co-chemotherapeutic agent on HeLa cell lines, it can exhibit potential abbility
with p53 stabilization. Further molecular target detection to investigate its
cellular pathway needs to be conducted (5).

Colon Cancer:

In a study performed by Jaramillo MC et al., the mechanism of action of ethyl
acetate extract of A. muricata leaves against colon cancer
cells (HT-29 and HCT-116) and lung cancer cells (A549) has been illustrated.
The leaf extract was proficient to induce apoptosis in colon and lung cancer
cells through the mitochondrial-mediated pathway. This anti-proliferative
effect was alongside with cell cycle arrest in the G1 phase (21). However, the migration and
invasion of colon cancer cells were profoundly inhibited by the leaf extract. The in vivo chemo preventive potential of the ethyl
acetate extract of the A. muricata leaves against azoxymethane-induced
colonic aberrant crypt foci (ACF) in rats was validated by Moghadamtousi and
colleagues(31). Oral dosage that was administered for 60days
caused a significant reduction of ACF formation in rats when tested by
methylene blue staining of the colorectal specimens. PCNA and Bcl2 proteins
were down regulated whereas Bax protein was up regulated after the
administration of the extract. This was depicted in the immunohistochemistry analysis where they were compared with cancer
control group. In addition the levels of enzymatic antioxidants showed an increase
and a suppression was seen in malondialdehyde level of the colon tissue
homogenates. This suggested the restraint of lipid peroxidation. An AGE
annomuricin E was found to inhibit the growth of HT-29 cells. The cytotoxic
effect of annomuricin E was enhanced by the G1 cell cycle arrest. Annomuricin
activated the mitochondrial events comprising the dissipation of the
mitochondrial membrane potential and caused the leakage of cytochrome c from
the mitochondria. Followed by this, annomuricin E activated caspase 3/7 and
caspase 9 responsible for the apoptosis (42). Furthermore, Moghadamtousi and colleagues
examined that ethyl acetate extract of Annona muricata leaves
(EEAM) exerted a striking cytotoxic effects on HCT-116 cells as determined by
MTT and LDH assays. Flow cytometric analysis illucidated the cell cycle arrest
at G1 phase and also the externalization of phosphatidylserine
acting as an indicator of the induction of apoptosis. EEAM treatment activated
excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage
and activation of the initiator and executioner caspases in both colon cancer
cells. These processes subsequently steer to attenuation
of mitochondrial membrane potential (MMP) and cytochrome c release. Release of
cytochrome c activates apotosome and the intrinsic caspase cascade that
triggers execution of apoptosis through DNA fragmentation. Immunofluorescence analysis portrayed the
up-regulation of Bax and down-regulation of Bcl-2 proteins while treated with
EEAM. Furthermore, EEAM conspicuously blocked the migration and invasion of
HT-29 and HCT-116 cells. (32, 33, 34).  Thus, these findings verify
the usage of A. muricata leaves in ethnomedicine against cancer and emphasize
annomuricin E as one of the contributing compounds in the anticancer activity
of A. muricata leaves.

Leukemia:

Investigations
have also been done to check the ability of ethanolic extracts of Annona muricata leaves for its
cytotoxicity potential and capacity of inducing apoptosis in K562 cancer cells,
a chronic myelogenous cell line.
The activity of Caspase-3 was remarkably enhanced during the apoptosis
stimulated by the extract at a low quantity. Terminal deoxynucleotidyl
transferase-mediated dUTP nick-end labelling (TUNEL) assay results verified the
process of apoptosis. The Caspase-3 activity and TUNEL assay reports endorsed
that the ethanolic extract of A. muricata
leaves induced apoptosis in K562 cell lines. Ezirim, A U and colleagues
thus concluded in their paper that Annona
muricata could be considered as a natural source for the preparation of pro
apoptotic drugs(16). Also in the reports
by, Constant Anatole Pieme and others, A. muricata had exhibited anti proliferative effects on HL-60
cells (Human promyelocytic leukemia cell line) by promoting the loss of
cell viability, morphological differences, loss in membrane mitochondrial
potential and G0/G1 phase cell arrest. Their conclusions confirmed the efficacy
of A. muricata as an agent of chemotherapeutic and cytostatic
activity in HL-60 cells (8).

 

 

Liver Carcinoma:

The aqueous extracts of Annona muricata was tested for the
activation of caspases in Huh-7 (human liver cancer cells). Huh-7 cells when
treated with the extracts, both caspase-9 and caspase-3 activities in the cells
were uplifted. This suggested that the extract had induced apoptosis by
activating the mitochondrial mediated intrinsic pathway. The protein analysis
(western blot) of caspases demonstrated that the expressions of the cleaved
caspases was dose dependent. Considering these results, it was concluded that
the extract of A.muricata leaves have
a good potential to play a vital role as cancer chemotherapeutic agents.
Furthermore, the reports by Banerjee A. et,al. indicate the reduction in the
viability of hepatocellular carcinoma cell lines possibly through G0/G1 or S phase arrest or via induction of
sub-G0/G1 DNA fragmentation thus supporting the anti-cancerous property of A.muricata.(6).

Lung Cancer:

The A549 cells
(adenocarcinomic human alveolar basal epithelial cells) when treated with
aqueous extracts of A. muricata
showed elevated levels of ROS, reduction of MMP (matrix metalloproteinases)
through the upheaval of expression of Bax and decreased expression of Bcl-2.
These events led to the release of cytochrome c release to the cytosol. The
released cyt-c activated caspase-9
and caspase-3, thus causing apoptosis. Concomitantly, there was a cell cycle
arrest at G0G1 phase. The incubation of A549 cells with superoxide dismutase
and catalase predominantly suppressed the cytotoxicity that was induced by the
extract. This highlighted that the intracellular ROS plays an important role in
cell death. Anonna muricata also has had impacts on Lewis lung carcinoma (LLC)
tumor cell lines that were examined both in
vivo as well as in vitro was
shown in a study by Zhao GX1 et,. al. This
validated that Graviola had antitumor activity by limiting the natural growth
of the lung tumors (47)
NADH oxidase inhibition
in cancer cell lines, down regulation of the P-glycoprotein pump via ATP
depletion and Cell cycle arrest at S-phase progression has shown to be affected
by Graviola through its anti-cancerous and cytotoxic mechanisms, which has been
shown by additional research (45).  

Ovarian Cancer:

Other than its various medicinal properties,
the acetogenins of Annona muricata
have showed potent anti-ovarian cancer activity which specifically attack
cancerous cells without affecting the healthy cells and prevent metastasis. The
plant has been proven to be an effective anti-tumor and anti-cancer medicinal
plant, and thus represents a source for new antiovarian cancer drug discovery.
Cytotoxicity tests were performed in vitro using MTT assay as described Cletus
A. et,al. In vivo pilot experiment experiment was performed with thirty Swiss
albino mice consisting of all females (average weights 18-25g). The mice were
injected with 1 x 104 OV7-96020764-CDNA-(20uL) cell line intraperitoneally into
the abdominal cavity to form ascites which mimicked ovarian cancer. Once the
ascites were formed, 5 groups of mice were examined of which 4 were control, 12
were treated with the leaf extract of A.
muricata and 4 were treated with doxorubicin. It was remarkably noted that
the Annona muricata
extract had inhibited tumor growth in a mouse model with intraperitoneal
metastasis ascites formation. Above 90% of 
the tumor inhibition has been succefully achieved using Annona muricata (7)..

Pancreatic Cancer (PC):

Pancreatic tumor aggressiveness is allied
with a heightened metabolic activity and glucose concentration of malignant
tumors(43). Also a hypoxic environment has been proven to be necessary
for the oncogenic and metabolic transformation and the survival of the pancreatic
cancer cells. In particular, it is believed that resistance to drugs is
induced by hypoxia by the activation of PI3K, Akt, NF-?B and MAPK pathways(15).  The cells after being treated with the Graviola
extract, showed low viability as the phosphorylation of the molecules was
hindered by the extract. Accordingly, the major transcription factor that is
activated under hypoxic conditions, HIF-1a expression was investigated. The
reports stated that a product of the extract had blocked glucose transporters
(GLUT1 and GLUT4), NF-?B,
HIF-1a and other glycolytic enzymes like LDHA, which reduced the uptake of
glucose molecules and the production of ATP by the PC cells. This overall
reduction caused the cell death. In accord with the ATP reduction, the extract
also increased the ROS levels within the cells that eventually led to necrosis(41, 30). Necrotic
agents by itself being less significant in the treatment of cancer as they
induce a local inflammation. But the inflammation thus caused leads to the
activation of the innate immune system to initiate anti-tumor activities (41). This effect
along with the progression of PC cells was evaluated in the KrasG12DPdx1- Cre
mice(36,40). The mice
with a developing pancreatic intraepithelial neoplastic (PanIN) lesions was fed
with the plant extract. The cells were analyzed and it was concluded that the
cytotoxic effects were particular to the tumor cells. Thus the administration
of Graviola caused glycolytic inhibition was seen in the PC cells that led to
the depletion of the tumor.

Prostate Cancer

The anti-proliferative effects of the water
extract of leaves of A. muricata was examined in vivo against the benign
prostatic hyperplasia (BPH-1) cell line and the rat prostates were observed.
Normal histology of all the other testes was observed. There was a significant
reduction in the size of the seminal vesicles of the test groups and displayed
a remarkable atrophy with a raised cellularity and zero secretion in the
acinii. The apoptotic characteristics of the glandular epithelium was typically
seen (pycknotic nuclei and nuclear material towards the periphery). Also, the
Bax protein was up regulated, while Bcl-2 was suppressed. Thus it was concluded
that Annona muricata
has anti-proliferative effects on BPH-1 cells and deduces the prostate size,
possibly through apoptosis (4).
The effect of Graviola extract against the
prostate cancer cell lines has also been expounded in vitro. Experiments have
been performed to show that Graviola initiates necrosis in PC-3 cells through
the inhibition of cellular metabolism and tumor mobility. Further evaluation
depicted the downregulation of the expression of the hypoxia-related factors
and glycolytic factors following treatment in PC cells with Graviola (41). The
inhibition of prostate cancer proliferation, viability and clonogenic colonies
have been proved as an outcome of the Graviola leaf extract (GLE)
pharmacokinetics and absorption kinetics (43).