In foci (ACF) in rats was examined

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 (20). However, the
migration and invasion of colon cancer cells were profoundly inhibited by the
leaf extract.

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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 examined by Moghadamtousi and
colleages. There was a significant reduction in ACF formation in rats because
of the oral administration of the extract at two doses (250 and 500 mg/kg) for
60 days, as gaged by methylene blue staining of colorectal specimens. The down-regulation of PCNA and Bcl-2 proteins and
the up-regulation of Bax protein after the administration of EEAML compared
with the cancer control group was depicted in the Immunohistochemistry
analysis. In addition, an increase
in the levels of enzymatic antioxidants and a reduction in the malondialdehyde
level of the colon tissue homogenates were found, suggesting the suppression of
lipid peroxidation. The growth of HT-29 cells with an IC50 value of 1.62 ± 0.24
?g/ml after 48 h was inhibited by Annomuricin E. The cytotoxic effect of
annomuricin E was supplementarily substantiated by G1 cell cycle arrest and
early apoptosis induction in HT-29 cells. Annomuricin E activated
mitochondria-initiated events, comprising the dissipation of the mitochondrial
membrane potential and caused the leakage of cytochrome c from the
mitochondria. Preceding these events, annomuricin E activated caspase 3/7 and
caspase 9. Further annomuricin E, induced a time-dependent upregulation of Bax
and downregulation of Bcl-2 at the mRNA and protein levels. 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. Furthermore, Moghadamtousi and colleagues examined that ethyl
acetate extract of Annona muricata leaves (EEAM) exerted a
striking cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT and
LDH assays. After 24 h of treatment, EEAM showed the IC50 value
against HT-29 and HCT-116 cells. 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. 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 (29,31).

In colon cancer cells, Graviola leaves also
have significant effects on cell survival potential via mitochondrial-mediated
apoptosis associated with the G1 cell cycle arrest. Graviola elicits apoptosis
by generating reactive oxygen species ROS and down-regulating the
anti-apoptotic Bcl-2 protein, while up-regulating pro-apoptotic Bax protein.
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. (30). Further
studies by Yang C et, .al have
shown that the Graviola leaf extract (GLE) pharmacokinetics and absorption
kinetics resulting in inhibiting prostate cancer proliferation, viability and
clonogenic colonies (43).