Oxalomalate, a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase, regulates heat shock-induced apoptosis.

Abstract

Heat shock may increase oxidative stress due to increased production of reactive oxygen species and/or the promotion of cellular oxidation events. Recently, we demonstrated that the control of cytosolic and mitochondrial redox balance and the cellular defense against oxidative damage is one of the primary functions of NADP(+)-dependent isocitrate dehydrogenase (ICDH) by supplying NADPH for antioxidant systems. The protective role of ICDH against heat shock-induced apoptosis in U937 cells was investigated in the control and the cells pre-treated with oxalomalate, a competitive inhibitor of ICDH. Upon exposure to heat shock, there was a distinct difference between the control cells and the cells pre-treated with 3mM oxalomalate for 3h in regard to apoptotic parameters, cellular redox status, and mitochondrial function. The oxalomalate pre-treated cells showed significant enhancement of apoptotic features such as activation of caspase-3, up-regulation of Bax, and down-regulation of Bcl-2 compared to the control cells upon exposure to heat shock. This study indicates that ICDH may play an important role in regulating the apoptosis induced by heat shock presumably through maintaining the cellular redox status.

• Authors: Hyun Jeong Kim, Jeen-Woo Park
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 337 Issue 2 Pg. 685-91 (Nov 18 2005) ISSN: 0006-291X [Print] United States
• PMID: 16202391 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Oxalates
• Proto-Oncogene Proteins c-bcl-2
• oxalomalic acid
• NADP
• Isocitrate Dehydrogenase
• CASP3 protein, human
• Caspase 3
• Caspases

Topics

• Apoptosis (drug effects)
• Caspase 3
• Caspases (metabolism)
• Down-Regulation
• Enzyme Inhibitors (pharmacology)
• Heat-Shock Response (drug effects, physiology)
• Humans
• Isocitrate Dehydrogenase (antagonists & inhibitors)
• NADP (metabolism)
• Oxalates (pharmacology)
• Oxidation-Reduction
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• U937 Cells
• Up-Regulation