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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

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Title 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
 
Creator Khan, Sheema
Kaur, Rajbir
Shah, Bhahwal A.
Malik, Fayaz
Kumar, Ajay
Bhushan, Shashi
Jain, S.K.
Taneja, Subhash C.
Singh, Jaswant
 
Subject Pharmacological Sciences
 
Description 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.
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://iiim.csircentral.net/188/1/10.1002mc.20821.pdf
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
 
Relation http://dx.doi.org/10.1002/mc.20821
http://iiim.csircentral.net/188/