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

Sheema Khan, Rajbir Kaur, Bhahwal A. Shah, Fayaz Malik, Ajay Kumar, Shashi Bhushan, S. K. Jain, Subhash C. Taneja, Jaswant Singh

Research output: Contribution to journalArticle

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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-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 48h IC 50 of 0.67μM in HL-60, 1μM in Molt4, and 1.5μM 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.

Original languageEnglish (US)
Pages (from-to)679-695
Number of pages17
JournalMolecular Carcinogenesis
Volume51
Issue number9
DOIs
StatePublished - Sep 1 2012

Fingerprint

Phosphatidylinositol 3-Kinase
HL-60 Cells
Cause of Death
Cell Survival
Apoptosis
Caspase 8
Caspase Inhibitors
Caspase 9
Caspase 3
Small Interfering RNA
Neoplasms
Caspases
Cytochromes c
11-keto-boswellic acid
Cytosol
Mitochondria
Leukemia
Cell Death
Cell Proliferation
Cell Line

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

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. / Khan, Sheema; Kaur, Rajbir; Shah, Bhahwal A.; Malik, Fayaz; Kumar, Ajay; Bhushan, Shashi; Jain, S. K.; Taneja, Subhash C.; Singh, Jaswant.

In: Molecular Carcinogenesis, Vol. 51, No. 9, 01.09.2012, p. 679-695.

Research output: Contribution to journalArticle

Khan, Sheema ; Kaur, Rajbir ; Shah, Bhahwal A. ; Malik, Fayaz ; Kumar, Ajay ; Bhushan, Shashi ; Jain, S. K. ; Taneja, Subhash C. ; Singh, Jaswant. / 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. In: Molecular Carcinogenesis. 2012 ; Vol. 51, No. 9. pp. 679-695.
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AU - Shah, Bhahwal A.

AU - Malik, Fayaz

AU - Kumar, Ajay

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AU - Jain, S. K.

AU - Taneja, Subhash C.

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