Kumar, Ajay and Malik, Fayaz and Bhushan, Shashi and Shah, Bhahwal A. and Taneja, Subhash C. and Pal, Harish C. and Wani, Zahoor A. and Mondhe, Dilip M. and Kaur, Jagdeep and Singh, Jaswant (2011) A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells. Chemico-Biological Interactions, 193 (3). pp. 204-215. ISSN 00092797

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Abstract

This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48 h IC50 of 3.5 lM. At 10 mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25 mg/kg it inhibited Ehrlich ascites tumor growth by 60%.Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-L-cysteine(NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-jB (p65) was cleaved with a simultaneous increase in cytosolic IjB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multimodal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic.

Item Type:	Article
Subjects:	Pharmacological Sciences
Divisions:	UNSPECIFIED
Depositing User:	Mr. Amit Nargotra
Date Deposited:	19 Dec 2011 07:43
Last Modified:	19 Dec 2011 07:43
URI:	http://iiim.csircentral.net/id/eprint/191

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