There effects. (32) Constant examinations on diverse parts

There are more than 200 chemical compounds
that have been documented and isolated from this plant; the foremost being 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.
Studies on the extracts and isolated compounds of A. muricata showed contraceptive, antitumor, anti-ulceric, wound
healing, hepato-protective, anxiolytic, anti-stress, anti-inflammatory,
anti-icteric and hypoglycemic activities. Furthermore, there have been clinical
studies carried out in order to boost the hypoglycemic activity of the
ethanolic extracts of A. muricata
leaves. Mechanisms of action of a few pharmacological activities have been
explicated, such as cytotoxic, antioxidant, antimicrobial, anti-nociception and
hypotensive activities. Nonetheless, some phytochemical compounds isolated from
A. muricata have shown a neurotoxic
effect in vitro and in vivo. Thus, these crude extracts and isolated compounds
requires further studies to define the magnitude of the effects, optimal
dosage, long-term safety, and potential side effects. (32)

examinations on diverse parts of the A. muricata have shown the
occurrence of varieties of phyto constituents and compounds, including flavonol
triglycosides (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 the 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. (23,25,26,28,35,42)

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Acetogenins are a
unique category of C-35/C37 secondary metabolites obtained from long chain
(C-32/C34) fatty acids in the polyketide pathway. They are basically illustrated
by combining fatty acids with  2-propanol
unit at C-2 that gives a methyl-substituted ?, ?-unsaturated ?-lactone.
Starting with the discovery of uvaricin from Uvaria accuminata in
1982,there have been several acetogenins that are identified. About 500 have
been reported from numerous parts of the plants in the Annonaceae family.
Because of the exceptional structures and broad spectrum of biological
activities, AGEs have drawn significant scientific interest of late. The active
annonaceous acetogenins have shown to be successful in inducing death in cancer
cells that are resistant to even chemotherapeutic drugs. Besides their
remarkable anti proliferative efficacy, these annonaceous acetogenins have been
endorsed to debilitating side effects such as neurotoxicity suggesting that
these components can easily traverse the blood–brain barrier and are known to
cause atypical Parkinson’s disease, thus restricting their development as new
drug entities. Various biological activities have been reported for AGEs,
including antimalarial, anti-parasitic and pesticidal activities. However, the
physiological activities of AGEs are initially characterized by the toxicity
against cancer cells and inhibitions of the mitochondrial complex I. (11)

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:

In the conclusions made by, Constant Anatole Pieme and
others A. muricata exhibited
anti proliferative effects on HL-60 cells by promoting loss of cell viability,
morphology changes, loss of membrane mitochondrial potential and G0/G1 phase
cell arrest. Their reports confirmed the efficacy of A. muricata as
an agent of chemotherapeutic and cytostatic activity in HL-60 cells (7). Studies have revealed
that the extracts have selective inhibition of breast cancer cells via EGFR
downregulation. An oncogene, the epidermal growth factor receptor (EGFR) is
that is often overexpressed in breast cancer (BC), along with its
overexpression has been associated with poor prognosis and drug resistance.
EGFR is therefore a rational target for BC therapy development. In addition,
experiments showed that Graviola fruit extract (GFE) reduces the growth of BC
cells utilizing xenografts mouse model studies. Moreover, GFE selectively
restrained the growth of EGFR-overexpressing human BC (MDA-MB-468) cells but
not in non-tumorigenic human breast epithelial cells (MCF-10A). These studies strengthen the
evidence that Graviola has selective anti-growth effects between cancer and
non-cancer cells (8).

Another report
on breast cancer cells by Yu-Min Koa and
colleagues supported that Graviola endorses apoptosis in ER-related
pathways. Moreover, Graviola subsided MCF-7 tumor growth while hindering
ER-cyclin D1 and Bcl-2 protein expressions in nude mice (44). It has been analyzed that Graviola also seemed
to have anti-proliferative effects of HL-60 cells via loss of cell viability,
loss of MMP, G0/G1 phase cell arrest and morphological apoptotic changes. It
was authenticated and confirmed that Graviola does indeed have
anti-proliferative and cytostatic activity in HL-60 cells by these findings


Lung Cancer:

of A549 cells with AMEAE significantly elevated ROS formation, followed by
attenuation of MMP via upregulation of Bax and downregulation of Bcl-2,
accompanied by cytochrome c release to the cytosol. The incubation of A549
cells with superoxide dismutase and catalase significantly attenuated the cytotoxicity
caused by AMEAE, indicating that intracellular ROS plays a pivotal role in cell
death. The released cytochrome c triggered the activation of caspase-9 followed
by caspase-3. In addition, AMEAE-induced apoptosis was accompanied by cell
cycle arrest at G0/G1 phase. Moreover, AMEAE suppressed the induced
translocation of NF-?B from cytoplasm to nucleus. Anonna muricata also had impacts on Lewis lung carcinoma (LLC)
tumor cell lines that were examined both in
vivo as well as in vitro which
was shown in an another study by Zhao GX1
et,.al. This implies that Graviola had antitumor activity by limiting
the natural growth of the lung tumors (45). 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.  

Liver Carcinoma

In the present
study, we researched whether different concentrations of aqueous extract of Annona muricata can activate the
caspases in Huh-7 human liver cancer cells. The activity of both caspase-9 and
caspase-3 were fundamentally lifted when Huh-7 cells were treated with 0.5
mg/ml, 1.0 mg/ml and 1.5 mg/ml of AEAML, suggesting that the plant extract has
induced apoptosis predominantly via mitochondrial-mediated intrinsic pathway.
The western blot analysis of caspases likewise demonstrated that the protein
expression of cleaved caspase-3 and -9 were dose-dependently increased upon
treatment with the AEAML. In the present study, the caspase 3 and caspase 9
expressions were increased significantly in Huh-7 cells treated with graded
increasing doses of the aqueous extract of Annona
muricata. This result suggests the involvement of caspase cascade in
aqueous extract of Annona muricata mediated
apoptosis in Huh-7 cells.

Taking everything into account, results of this
study demonstrate that the extract of Annona
muricata leaves possess good potential for use as cancer chemotherapeutic agent. Furthermore, our data indicate that the
aqueous extract of Annona muricataleaves
specifically reduce viability of hepatocellular carcinoma cell lines possibly
through G0/G1 or S phase arrest or possibly via induction of sub-G0/G1 DNA
fragmentation. Be that as it may, the mechanism of the action is still pending.
Along these lines, further investigation of the molecular mechanism(s) involved
is needed to fully understand the use of Annona
muricata as a chemopreventive food.

Pancreatic Cancer:

patients, an increased metabolic activity and glucose concentration of
malignant tumors has been linked to pancreatic tumor aggressiveness 47.
Additionally, the presence of hypoxia in PC has been associated with tumor
growth and metastasis 48,49. Indeed, the presence of hypoxic environment has
been linked to the oncogenic and metabolic transformation (i.e. glycolysis) of
PC cells that results in resistance to conventional cancer therapeutics
48,50. More specifically, it has been suggested that hypoxia can induce
resistance to gemcitabine through the activation of PI3K/Akt/NF-jB and MAPK/ERK
pathways 51, which are also related to PC progression and survival. The
activation of both of these signaling pathways was evaluated in PC cells after
treatment with Graviola extract and it was found that the extract suppressed
phosphorylation of the key molecules involved in these pathways, which
correlated with reduced viability of PC cells. Subsequently, the expression of
HIF-1a, the major transcription factor activated under hypoxic conditions, and
its ensuing downstream effects on PC cell metabolism were analyzed in Graviola
extract treated cells. The results indicated the natural product inhibited PC
cell metabolism by inhibiting the expression of HIF-1a, NF-jB, glucose
transporters (i.e. GLUT1, GLUT4), and glycolytic enzymes (i.e. HKII, LDHA), all
of which lead to the reduction of glucose uptake and ATP production by PC
cells. The overall downregulation of PC cell metabolism induced by Graviola
extract resulted in PC cell death and necrosis. In agreement with previous
studies of ATP reduction, the metabolic and therapeutic stress induced by
Graviola extract led to an acute ATP depletion, which is accompanied by increased
intracellular ROS, ultimately leading to necrosis 52–54. While necrotic
agents have not been considered beneficial in cancer therapies due to induction
of local inflammation, the process itself can lead to the activation of the
innate immune system capable of initiating anti-tumor immunity 52. It makes
it imperative to evaluate the effect of a necrosis-inducing product such as
Graviola extract in an immune competent host. In this regard, we plan to
evaluate the effect of the natural product on the progression of pancreatic
adenocarcinoma in the KrasG12DPdx1- Cre spontaneous animal model, where the
effect on the immune system can be evaluated 55,56. In order to evaluate the
potential of Graviola extract in preventing PC progression, we plan to supplement
the diet of KrasG12DPdx1-Cre mice with Graviola extract after the mice start
developing pancreatic intraepithelial neoplastic (PanIN) lesions. The effective
concentrations of Graviola metabolites after oral absorption and effects on the
immune system will be measured as well. Additional experiments will be carried
out to evaluate the potential of a combination therapy of Graviola extract with
the standard chemotherapeutic drug Gemcitabine. With the results discussed in
the present study, it is expected that minimum doses of the chemotherapeutic
drug will be needed to eradicate the malignant disease. The major bioactive
compounds identified in A. Muricata have been classified as Annonaceous
acetogenins, which inhibit mitochondrial complex I that leads to a decreased
ATP production 13–17. Although the natural extract capsules used in these
studies contained numerous compounds, the presence of Annonaceous acetogenins
was evident by the depletion of ATP production in PC cells after being
incubated with Graviola extract. Bioactivityguided fractionation for the
identification of potent bioactive (i.e. anti-tumorigenic) compounds that are
present in the Graviola extract is currently being investigated. We are also
ensuring that cytotoxic effects are specific to tumorigenic cells only, by
including the non-transformed immortalized pancreatic epithelial cell line
HPNE, which is derived from pancreatic duct (data not shown). Pancreatic tumors
develop from a complex interplay of numerous signaling pathways and Graviola
extract has shown promising anti-tumorigenic characteristics by targeting some
of these pathways all at once. Although novel glycolytic inhibitors, such as
Graviola extract, may have broad therapeutic applications 57, inhibition of
glycolysis alone may not be sufficient to eradicate tumor cells completely.
Perhaps the use of alternative medicine, like taking Graviola capsules on a
regular basis, should still be considered a supplement, not a replacement for
standard therapies.

Prostate Cancer

The activity of the water extract of leaves
of A. muricata against the benign prostatic hyperplasia
(BPH-1) cell line and rats prostates was examined where the the
anti-proliferative effects with an IC50 of 1.36 mg/mL was indicated. Bax gene
was up regulated, while Bcl-2 was suppressed. Normal histology of all the other
testes was observed. Seminal vesicle was significantly reduced in test groups
during apoptosis induced by the extract at low quantities, with the peak
activity shown at 50 µg/ml. Apoptosis was confirmed by terminal
deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay.
Caspase-3 activity and TUNEL results suggested that the ethanolic extract of
Annona muricata induced apoptosis in the myelogenous leukemic K562 cell line.
This supports the therapeutic application of Annona muricata to be considered
as a natural product source for the development of pro-apoptotic drugs

Cervical Cancer:

result demonstrated that polyketide derivatives from Annona muricata L. have
growth inhibitory and cytotoxic effect on cervical cancer cell line. Polyketide
derivatives from Annona muricata L. leaves performed potent cytotoxic effect on
Hela cells with IC50 value of 77,09 µg/ml. 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 suppresor protein. In this study, we observed that
polyketide derivative from Annona muricata L. treatment increased p53 level in
nucleus. Therefore, poliketide isolation may be amandable as viral inhibitor
agent and as competitor of vaccine to prevent the development of cervical
cancer. However, this speculation still needs further investigation by in
silico study. In conclusion, polyketide derivatives from Annona muricata L.
leaves indicate 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.

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