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Inhibition of Glutathione Synthesis Overcomes Bcl-2-Mediated Topoisomerase Inhibitor Resistance and Induces Nonapoptotic Cell Death via Mitochondrial-Independent Pathway

¹ First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan and ² Department of Genetics, National Research Institute for Child Health and Development, Tokyo, Japan

Requests for reprints: Akira Yoshida, First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka, 910-1193 Fukui, Japan. Phone: 81-776-61-8345; Fax: 81-776-61-8109; E-mail: ayoshi{at}fmsrsa.fukui-med.ac.jp.

Bcl-2 protein plays a critical role in inhibiting anticancer drug–induced apoptosis. We found that Bcl-2 overexpression is associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after treatment with etoposide or SN-38, a derivative of camptothecin, in leukemia 697 cells with wild-type p53. Treatment of Bcl-2-overexpressing 697 cells (697-Bcl-2) with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, reduced cellular glutathione levels and completely abolished Bcl-2-mediated drug resistance. Morphologic studies revealed that nonapoptotic cell death was induced in 697-Bcl-2 cells after treatment with BSO plus etoposide or SN-38. Activation of caspase-3/7 and cytochrome c release could not be detected in 697-Bcl-2 cells after these drug treatments. Notably, we showed that proteasome-mediated down-regulation of Puma and Noxa proteins occurs in 697-Bcl-2 cells after treatment with BSO plus topoisomerase inhibitor, although there is an increase in the protein levels of p53 in these 697-Bcl-2 cells. In contrast, parental 697 cells underwent typical apoptosis with up-regulation of Puma and Noxa proteins, followed by cytochrome c release and caspase-3/7 activation after treatment with topoisomerase inhibitor in the presence or absence of BSO. Our data suggest that BSO may possess a unique activity to overcome Bcl-2-mediated drug resistance by stimulating the signals that can bypass mitochondrial process in Bcl-2-overexpressing cells. (Cancer Res 2006; 66(11): 5772-80)

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