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J. Biol. Chem. 277 (4): 2554-2561

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Methylglyoxal Enhances Cisplatin-induced Cytotoxicity by Activating Protein Kinase Cdelta *

Jonathan P. Godbout, James Pesavento, Matthew E. Hartman, Scott R. Manson, and Gregory G. FreundDagger

From the Departments of Pathology and Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

The cytotoxic side effects of anti-neoplastic drugs are increased in patients with either type 1 or type 2 diabetes mellitus by a mechanism that is not clearly defined. We report that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta ). We found that treatment of myeloma cells with the antioxidant N-acetylcysteine completely blocked cisplatin-dependent intracellular GSH oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Importantly, co-treatment of cells with the reactive carbonyl MGO and cisplatin increased apoptosis by 90% over the expected additive effect of combined MGO and cisplatin treatment. This same synergism was also observed when ROS generation was examined. MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC. Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis. Finally, MGO and cisplatin induced c-Abl activation and c-Abl:PKCdelta association. Rottlerin blocked c-Abl activation, but the c-Abl inhibitor STI-571 increased MGO and cisplatin-induced apoptosis by 50%. Taken together these data indicate that MGO synergistically enhances cisplatin-induced apoptosis through activation of PKCdelta and that PKCdelta is critical to both cell death and cell survival pathways. These findings suggest that in the patient with diabetes mellitus heightened oxidative stress can enhance the cytotoxicity of agents that induce DNA damage.

* This work was supported by National Institutes of Health Grant CA-61931 (to G. G. F.), the Macula Foundation, Inc. (to G. G. F.), the American Diabetes Association (to G. G. F. and M. E. H), the American Heart Association (to G. G. F.), and United States Department of Agriculture/Cooperative State Research Education and Extension Service (CSREES), Hatch (to G. G. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence and reprint requests should be addressed: Dept. of Pathology, College of Medicine, 506 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, IL 61801. Tel.: 217-244-8839; Fax: 217-244-5617; E-mail: freun@uiuc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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