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ISSN: 2167-0501

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Research Article

Apoptosis and Differentiation of K562 Cells by Targeting GST-O1 to Inhibit 4-HNE Metabolism

Kathryn Leake1, Jyotsana Singhal1, Sharad S Singhal1 and Sanjay Awasthi1,2*
1Department of Diabetes, Endocrinology & Metabolism, California, USA
2Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California, USA
Corresponding Author : Sanjay Awasthi
Department of Medical Oncology and Experimental Therapeutics
City of Hope Comprehensive Cancer Center
Duarte, California
Tel: 626-256-4673
Fax: 626-301-8136
E-mail: [email protected]
Received June 20, 2014; Accepted July 21, 2014; Published June 28, 2014
Citation: Leake K, Singhal J, Singhal SS, Awasthi S (2014) Apoptosis and Differentiation of K562 Cells by Targeting GST-O1 to Inhibit 4-HNE Metabolism. Biochem Pharmacol 3:144. doi:10.4172/2167-0501.1000144
Copyright: © 2014 Leake K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Bcr-Abl kinase inhibitors are very effective drugs for treatment of chronic myelogenous leukemia (CML), but treatment options are limited and relatively ineffective for patients with de-novo or acquired resistance. The K562 human erythroleukemia cell line, derived from a pleural effusion during blast crisis of a CML patient, is very useful for studying hematopoietic differentiation because it undergoes differentiation and apoptosis in response to chemicals that propagate lipid-peroxidation. 4-hydroxynonenal (4-HNE), a reactive aldehyde produced from peroxidation of polyunsaturated fatty acids, is metabolized primarily by glutathione S-transferases (GSTs). 4-HNE causes differentiation, apoptosis and necrosis in K562 cells, but cannot be used as a drug for resistant CML because of its highly toxic nature. Present studies addressed the possibility of developing an alternative targeted treatment aimed at increasing intracellular 4-HNE through inhibition of GST. Because the major GST-isoenzymes in leukemia cells are also present in normal tissues, we explored the possibility of modulating cellular 4-HNE levels by inhibiting GST isozymes with high activity towards 4-HNE. Our studies identified the presence of the GSTO1 isoenzyme in K562 cells, demonstrated its activity towards 4-HNE, and showed that its depletion causes apoptosis, necrosis and differentiation of these cells. These effects of GSTO1 depletion appear to involve RUNX1 mediated transcriptional regulation of GM-CSF. These findings offer a new target for treatment of resistant CML.

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