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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
Author(s) -
Khan Sheema,
Kaur Rajbir,
Shah Bhahwal A.,
Malik Fayaz,
Kumar Ajay,
Bhushan Shashi,
Jain S.K.,
Taneja Subhash C.,
Singh Jaswant
Publication year - 2012
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20821
Subject(s) - apoptosis , biology , protein kinase b , caspase , pi3k/akt/mtor pathway , survivin , programmed cell death , cytochrome c , microbiology and biotechnology , poly adp ribose polymerase , intrinsic apoptosis , caspase 3 , apoptosis inducing factor , caspase 9 , caspase 8 , kinase , mitochondrion , cancer research , biochemistry , enzyme , polymerase
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‐β ‐ 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 IC 50 of 0.67 µM in HL‐60, 1 µM in Molt4, and 1.5 µM 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‐κB, 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 ΔΨ mt 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. © 2011 Wiley Periodicals, Inc.