Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model.

Abstract

Although cisplatin attacks various tumors with remarkable efficacy, its clinical usage has been limited by its side effects, particularly nephrotoxicity. Salubrinal, a selective eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation inhibitor, has been found to protect cells from endoplasmic reticulum (ER)-stress-induced cytotoxicity. In this study, we hypothesized that salubrinal would protect against cisplatin-induced nephrotoxicity in a mouse model. Cisplatin treatment significantly increased serum blood urea nitrogen and creatinine levels, renal kidney injury marker (kim-1) mRNA expression, renal cell apoptosis, and renal histopathological changes in mice. Unexpectedly, administration of salubrinal significantly enhanced the cisplatin-induced nephrotoxicity in mice. Salubrinal by itself did not induce alterations in the function or histomorphology of mouse kidneys. Salubrinal significantly enhanced the phosphorylation of eIF2α, the protein expression of activating transcription factor 4 and CCAAT/enhancer binding protein homologous protein, and the cleavage of caspases 12, 9, and 3 in the kidneys of cisplatin-treated mice. Moreover, salubrinal enhanced the cisplatin-induced oxidative stress in the kidneys. The antioxidant N-acetylcysteine significantly reversed the increased renal lipid peroxidation, activated renal caspase cascade, and increased blood BUN and creatinine in cisplatin-alone- or cisplatin plus salubrinal-treated mice. These findings suggest that salubrinal aggravates cisplatin-induced nephrotoxicity through the enhancement of oxidative stress and ER stress-related cell apoptosis.

• Authors: Cheng Tien Wu, Meei Ling Sheu, Keh Sung Tsai, Chih Kang Chiang, Shing Hwa Liu
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 51 Issue 3 Pg. 671-80 (Aug 01 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21616140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Cinnamates
• Eukaryotic Initiation Factor-2
• salubrinal
• Thiourea
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, pathology, physiopathology)
• Animals
• Apoptosis (drug effects)
• Cell Line
• Cinnamates (administration & dosage, adverse effects, pharmacology)
• Cisplatin (administration & dosage, adverse effects)
• Drug Synergism
• Eukaryotic Initiation Factor-2 (antagonists & inhibitors)
• Humans
• Kidney (metabolism, pathology)
• Mice
• Mice, Inbred ICR
• Models, Animal
• Oxidative Phosphorylation (drug effects)
• Oxidative Stress (drug effects)
• Thiourea (administration & dosage, adverse effects, analogs & derivatives, pharmacology)