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Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta
Jonathan P Godbout1, James Pesavento, Matthew E Hartman
1Department of Pathology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Abstract:
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.
Insights
Methylglyoxal (MGO), a glucose metabolite, synergistically enhances chemotherapy-induced apoptosis in cancer cells by activating protein kinase Cdelta (PKCdelta). This highlights a mechanism linking diabetes and increased anti-cancer drug toxicity.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Anti-neoplastic drugs exhibit increased cytotoxic side effects in diabetic patients.
- The underlying mechanism for this enhanced toxicity remains unclear.
- Methylglyoxal (MGO), a circulating glucose metabolite, is implicated in diabetic complications.
Purpose of the Study:
- To elucidate the mechanism by which methylglyoxal (MGO) influences cisplatin-induced apoptosis.
- To investigate the role of protein kinase Cdelta (PKCdelta) in MGO-enhanced cytotoxicity.
- To explore the interplay between oxidative stress, MGO, and anti-cancer drug effects.
Main Methods:
- Treatment of myeloma cells with cisplatin, MGO, N-acetylcysteine (NAC), rottlerin (PKCdelta inhibitor), and STI-571 (c-Abl inhibitor).
- Assessment of intracellular glutathione oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis.
- Measurement of PKCdelta and c-Abl activation and their association.
Main Results:
- MGO significantly potentiated cisplatin-induced apoptosis and ROS generation.
- N-acetylcysteine (NAC) blocked cisplatin-induced oxidative stress and apoptosis but not MGO-induced effects.
- PKCdelta activation was crucial for MGO and cisplatin-induced apoptosis and ROS generation, while c-Abl activation played a complex role.
- Inhibition of PKCdelta blocked apoptosis, whereas c-Abl inhibition enhanced it.
Conclusions:
- Methylglyoxal (MGO) synergistically enhances cisplatin-induced apoptosis via PKCdelta activation.
- PKCdelta is a critical mediator in both pro-apoptotic and pro-survival pathways.
- Heightened oxidative stress in diabetes may exacerbate the toxicity of DNA-damaging anti-cancer agents.