Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta.
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.
Godbout
Jonathan P
JP
Department of Pathology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Pesavento
James
J
Hartman
Matthew E
ME
Manson
Scott R
SR
Freund
Gregory G
GG
D000111:Acetylcysteine / Q000494:pharmacology; D017304:Annexin A5 / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D010545:Peroxides / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017304:Annexin A5; D000975:Antioxidants; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010545:Peroxides; D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D016315:Proto-Oncogene Proteins c-abl; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020169:Caspases; D005978:Glutathione; D002945:Cisplatin; D000111:Acetylcysteine