Khan, Sheema and Kaur, Rajbir and Shah, Bhahwal A. and Malik, Fayaz and Kumar, Ajay and Bhushan, Shashi and Jain, S.K. and Taneja, Subhash C. and Singh, Jaswant (2011) A Novel cyano derivative of 11-Keto-β-Boswellic acid causes apoptotic death by disrupting PI3K/AKT/Hsp-90 cascade, mitochondrial integrity, and other cell survival signaling events in HL-60 cells. Molecular Carcinogenesis. n/a-n/a. ISSN 08991987

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Abstract

Intervention of apoptosis is a promising strategy for discovery of novel anti-cancer therapeutics. In this study, we examined the ability of a novel cyano derivative of 11-keto-b-boswellic acid, that is, butyl 2-cyano-3,11-dioxours-1,12-dien-24-oate (BCDD) to induce apoptosis in cancer cells. BCDD inhibited cell proliferation with 48 h IC50 of 0.67 mM in HL-60, 1 mM in Molt4, and 1.5 mM in THP1 cells. The mechanism of cell death was investigated in HL-60 cells where it caused apoptosis by acting against several potential apoptosis suppressive targets. It inhibited phosphatidylinositol-3-kinase (PI3K)/AKT activity, NF-kB, Hsp-90, and survivin which may enhance the sensitivity of cells to apoptosis.Also, BCDD decreased the activity of Bid and Bax in cytosol, caused DCmt loss, releasing pro-apoptotic cytochrome c, SMAC/DIABLO leading to caspase-9-mediated down stream activation of caspase-3, ICAD, and PARP1 cleavage.Translocation of apoptotis-inducing factor (AIF) from mitochondria to the nucleus indicated some caspases-independent apoptosis. Though it upregulated DR-5 and caspase-8, the caspase inhibitor yet had no effect on apoptosis as against 75% inhibition by caspase-9 inhibitor. Attempts were made to examine any acclaimed role of AIF in the activation of caspase-8 using siRNA where it had no effect on caspase-8 activity while the Bax-siRNA inhibited caspase-3 activation suggesting predominance of intrinsic signaling. Our studies thus demonstrated that BCDD exerts multi-focal action in cancer cells while it required 10-fold higher the concentration to produce cytotoxicity in normal human PBMC and gingival cell line, and therefore, may find usefulness in the management of human leukemia.

Item Type:	Article
Subjects:	Pharmacological Sciences
Divisions:	UNSPECIFIED
Depositing User:	Mr. Amit Nargotra
Date Deposited:	19 Dec 2011 07:36
Last Modified:	19 Dec 2011 07:36
URI:	http://iiim.csircentral.net/id/eprint/188

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