2 research outputs found
18β-glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells
Triterpenes found in plants display a multitude of biological activities, including anti-tumor properties. The present study investigates the effect of 18β-glycyrrhetinic acid (GRA) a pentacyclic triterpenoid of the β-amyrin type, isolated from the root of Licorice (Glycyrrhizza glabra) on human breast cancer cells, MCF-7. GRA showed potent inhibitory effects on MCF-7 proliferation in a concentration- and time-dependent manner without affecting immortalized normal mammary epithelial cell line (MCF-10A). Growth inhibition of MCF-7 cells by GRA occurred through apoptosis, as evident from phosphatidyl serine externalization and DNA fragmentation. Apoptosis was primarily mediated through mitochondrial death cascade as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9. GRA induced an increase in Bax:Bcl-2 ratio along with a significant increase in the protein level of the BH3 protein Bim. SiRNA-mediated knock down of Bim markedly attenuated GRA-mediated apoptosis. Profiling of transcriptional regulators of Bim revealed a role of Forkhead box O 3a transcription factor (FOXO3a) as judged by increased expression and nuclear translocation of FOXO3a. Silencing of FOXO3a resulted in marked attenuation in the expression of Bim as well as protection against GRA-mediated apoptosis. Furthermore, GRA-induced activation and nuclear localization of FOXO3a was associated with a reduced activity of Akt kinase. These results suggest that GRA induces apoptosis in human breast carcinoma MCF-7 cells via caspase activation and modulation of Akt/FOXO3a pathway
Carnosic Acid Modulates Akt/IKK/NF-jB Signaling by PP2A and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis in Human Prostate Carcinoma PC-3 Cells
This study investigates the efficacy of carnosic
acid (CA), a polyphenolic diterpene, isolated from the plant
rosemary (Rosemarinus officinalis), on androgen-independent
human prostate cancer PC-3 cells. CA induced antiproliferative
effects in PC-3 cells in a concentration- and
time-dependent manner, which was due to apoptotic
induction as evident from flow-cytometry, DNA laddering
and TUNEL assay. Apoptosis was associated with the
activation of caspase-8, -9, -3 and -7, increase in Bax:Bcl-2
ratio, release of cytochrome-c and decrease in expression
of inhibitor of apoptosis (IAP) family of proteins. Apoptosis
was attenuated upon pretreatment with specific
inhibitors of caspase-8 (Z-IETD-fmk) and caspase-9 (ZLEHD-
fmk) suggesting the involvement of both intrinsic
and extrinsic apoptotic cascades. Further, apoptosis resulted
from the inhibition of IKK/NF-jB pathway as evident
from decreased DNA binding activity, nuclear translocation
of p50 and p65 and IjBa phosphorylation. The downregulation
of IKK/NF-jB was associated with inhibition of
Akt phosphorylation and its kinase activity with a concomitant
increase in the serine/threonine protein phosphatase
2A (PP2A) activity. Pharmacologic inhibition of PP2A
by okadaic acid and calyculin A, significantly reversed
CA-mediated apoptotic events in PC-3 cells indicating that
CA induced apoptosis by activation of PP2A through
modulation of Akt/IKK/NF-jB pathway. In addition, CA
induced apoptosis in another androgen refractory prostat cancer DU145 cells via intrinsic pathway as evidenced
from the activation of caspase 3, cleavage of PARP,
increase in Bax:Bcl-2 ratio and cytochrome-c release.
Carnosic acid, therefore, may have the potential for use in
the prevention and/or treatment of prostate cancer