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J. Biol. Chem., Vol. 278, Issue 39, 37832-37839, September 26, 2003

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Inhibition of Mitochondrial Respiration

A NOVEL STRATEGY TO ENHANCE DRUG-INDUCED APOPTOSIS IN HUMAN LEUKEMIA CELLS BY A REACTIVE OXYGEN SPECIES-MEDIATED MECHANISM^*

Hélène Pelicano , Li Feng , Yan Zhou , Jennifer S. Carew , Elizabeth O. Hileman , William Plunkett , Michael J. Keating ¶ and Peng Huang  ||

From the Departments of Molecular Pathology, Experimental Therapeutics, and ^¶Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Cancer cells are under intrinsic increased oxidative stress and vulnerable to free radical-induced apoptosis. Here, we report a strategy to hinder mitochondrial electron transport and increase superoxide radical generation in human leukemia cells as a novel mechanism to enhance apoptosis induced by anticancer agents. This strategy was first tested in a proof-of-principle study using rotenone, a specific inhibitor of mitochondrial electron transport complex I. Partial inhibition of mitochondrial respiration enhances electron leakage from the transport chain, leading to an increase in generation and sensitization of the leukemia cells to anticancer agents whose action involve free radical generation. Using leukemia cells with genetic alterations in mitochondrial DNA and biochemical approaches, we further demonstrated that As₂O₃, a clinically active anti-leukemia agent, inhibits mitochondrial respiratory function, increases free radical generation, and enhances the activity of another agent against cultured leukemia cells and primary leukemia cells isolated from patients. Our study shows that interfering mitochondrial respiration is a novel mechanism by which As₂O₃ increases generation of free radicals. This novel mechanism of action provides a biochemical basis for developing new drug combination strategies using As₂O₃ to enhance the activity of anticancer agents by promoting generation of free radicals.

Received for publication, February 13, 2003 , and in revised form, June 3, 2003.

^* This work was supported by Grants CA77339, CA85563, CA100428, and CA81534 from NCI, National Institutes of Health. 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.

^|| To whom correspondence should be addressed: Dept. of Molecular Pathology, Box 89, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-7742; Fax: 713-794-4672; E-mail: phuang{at}mdanderson.org.

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