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Research Paper

Anti-oxidant treatment enhances anti-tumor cytotoxicity of (-)-gossypol

Matthew J. Sikora, Joshua A. Bauer, ,Monique Verhaegen, Thomas J. Belbin, Michael B. Prystowsky, Joseph C. Taylor, J. Chad Brenner, Shaomeng Wang, Maria S. Soengas, Carol R. Bradford and Thomas E. Carey

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We showed that tumor cells with wild-type p53 and high levels of Bcl-xL are cisplatin resistant but are induced to undergo apoptosis by (-)-gossypol, making this a promising agent for overcoming cisplatin resistance. However, some cells in a population with this phenotype are not killed and continue to survive. Conversely, tumor cells with low Bcl-xL expression and either wild type or mutant p53 are relatively cisplatin sensitive and do not exhibit such high levels of apoptosis. However, these do undergo progressive loss of viability after (-)-gossypol that may not be tumor specific. We sought to elucidate the basis for these observations using cDNA microarray analysis of (-)-gossypol treated cisplatin sensitive and resistant cells. Genes in the reactive oxygen species (ROS) pathway were highly up-regulated in response to (-)-gossypol. The up-regulation was of much greater magnitude in cisplatin sensitive than resistant cells. Staining with an oxidation reporter dye confirmed differential induction of ROS in tumor cells with low Bcl-xL. As (-)-gossypol is known to undergo oxidative metabolism in vivo, ROS generation may be responsible for both off-target cytotoxicity and inactivation of the drug. In agreement with this hypothesis, oxidation of (-)-gossypol by pre-treatment with hydrogen peroxide eliminated its activity. Combined treatment with the antioxidant N-acetyl-cysteine (NAC) to block ROS increased (-)-gossypol-induced cytotoxicity to tumor but not normal cells. Furthermore, NAC increased the induction of apoptosis as measured by the sub G1 population, in both cisplatin sensitive and resistant cells. We postulate that concurrent treatment with antioxidant to block ROS prevents oxidative inactivation of (-)-gossypol and limits off-target toxicity allowing more potent (-)-gossypol-induced anti tumor activity.

Authors

Matthew J. Sikora

University of Michigan, Ann Arbor, MI

Joshua A. Bauer

University of Michigan, Ann Arbor, MI

,Monique Verhaegen

University of Michigan, Ann Arbor, MI

Thomas J. Belbin

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY

Michael B. Prystowsky

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY

Joseph C. Taylor

University of Michigan, Ann Arbor, MI

J. Chad Brenner

University of Michigan, Ann Arbor, MI

Shaomeng Wang

University of Michigan, Ann Arbor, MI

Maria S. Soengas

University of Michigan, Ann Arbor, MI

Carol R. Bradford

University of Michigan, Ann Arbor, MI

Thomas E. Carey

University of Michigan, Ann Arbor, MI

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.