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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.

The Journal of Biological Chemistry
|November 15, 2001
PubMed

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.

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