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J. Biol. Chem., Vol. 280, Issue 48, 40084-40096, December 2, 2005

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Endogenous Thioredoxin Is Required for Redox Cycling of Anthracyclines and p53-dependent Apoptosis in Cancer Cells^*

From the Department of Pathology and Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Apoptosis is a major mechanism of cancer cell destruction by chemotherapy and radiotherapy. The anthracycline class of antitumor drugs undergoes redox cycling in living cells producing increased amounts of reactive oxygen species and semiquinone radical, both of which can cause DNA damage, and consequently trigger apoptotic death of cancer cells. We show here that MCF-7 cells overexpressing thioredoxin (Trx) were more apoptotic in response to daunomycin. Trx overexpression in MCF-7 cells increased the generation of superoxide anion () in anthracycline-treated cell extracts. Enhanced generation of in response to daunomycin inTrx-overexpressing MCF-7 cells was inhibited by diphenyleneiodonium chloride, a general NADPH reductase inhibitor, demonstrating that Trx provides reducing equivalents to a bioreductive enzyme for redox cycling of daunomycin. Additionally Trx increased p53-DNA binding and expression in response to anthracyclines. MCF-7 cells expressing mutant redox-inactive Trx showed decreased superoxide generation, apoptosis, and p53 protein and DNA binding. In addition, down-regulation of endogenous Trx expression by small interfering RNA resulted in decreased expression of caspase-7 and cleaved poly(ADP-ribose) polymerase expression in response to daunomycin. These results suggest that endogenous Trx is required for anthracycline-mediated apoptosis of breast cancer cells. Taken together, our data demonstrate a novel pro-oxidant and proapoptotic role of Trx in anthracycline-mediated apoptosis in anthracycline chemotherapy.

Received for publication, July 1, 2005 , and in revised form, September 12, 2005.

^* This work was supported in part by a research project grant from the American Cancer Society (to K. C. D.) and National Institutes of Health Grant 1R01HL 071558 (to K. C. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 845, Little Rock, AR 72205. Tel.: 501-526-4597; Fax: 501-526-4601; E-mail: kdas{at}uams.edu.

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