Shashi, Bhushan and Jaswant, Singh and Madhusudana, Rao J. and Kumar, Saxena A. and Nabi, Qazi G. (2006) A novel lignan composition from Cedrus deodara induces apoptosis and early nitric oxide generation in human leukemia Molt-4 and HL-60 cells. Nitric Oxide, 14 (1). pp. 72-88. ISSN 10898603

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Abstract

AP9-cd, a standardized lignan composition from Cedrus deodara consisting of (¡)-wikstromal, (¡)-matairesinol, and dibenzyl butyrolactol,showed cytotoxicity in several human cancer cell lines reported earlier. An attempt was made in this study to investigate the mechanism of cell death in human leukemia Molt-4 and HL-60 cells. It inhibited Molt-4 cell proliferation with 48-h IC50 of »15 �g/ml, increased sub-G0 cell fraction with no mitotic block, produced apoptotic bodies and induced DNA ladder formation. Flow cytometric analysis of annexinV-FITC/PI-stained cells showed time-related increase in apoptosis and post-apoptotic necrosis. All these biological end-points indicated cell death by apoptosis. Further, initial events involved massive nitric oxide (NO) formation within 4 h with subsequent late appearance of peroxides in cells; measured by Xow cytometry using speciWc Xuorescent probes. Persistently high levels of NO and peroxide appeared to decrease mitochondrial membrane potential (�mt) which was recovered by cyclosporin A in Molt-4 cells. AP9- cd caused 2-fold activation of caspase-3 in Molt-4 and 5-fold activation in HL-60 cells. Also caspases-8 and -9 were activated in HL-60 cells. Ascorbate suppressed the enhanced caspases activities indicating a pro-oxidant eVect of AP9-cd. Further, caspase-3 activation correlated with NO generation that was partially impaired by nitric oxide synthase (NOS) inhibitors and ascorbate suggesting a role of prooxidant species in caspase-3 activation. AP9-cd produced no cytotoxicity in primary rat hepatocyte culture at the concentrations used. The studies indicated that AP9-cd mediated early NO formation leads to caspases activation, peroxide generation, and mitochondrial depolarization which may be responsible for mitochondrial-dependent and -independent apoptotic pathways involved in the killing of leukemia cells by AP9-cd

Item Type:	Article
Subjects:	Pharmacological Sciences
Divisions:	UNSPECIFIED
Depositing User:	Mr. Amit Nargotra
Date Deposited:	19 Dec 2011 07:41
Last Modified:	19 Dec 2011 07:42
URI:	http://iiim.csircentral.net/id/eprint/190

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