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Toxicol Appl Pharmacol. 2018 Jun 15;349:83-93. doi: 10.1016/j.taap.2018.04.010. Epub 2018 Apr 18.

N-acetylcysteine transforms necrosis into apoptosis and affords tailored protection from cisplatin cytotoxicity.

Author information

1
Institute of Biomedical Research of Salamanca (IBSAL), Spain; Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain; Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Valladolid, Spain.
2
Institute of Biomedical Research of Salamanca (IBSAL), Spain; Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain; Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain.
3
Institute of Biomedical Research of Salamanca (IBSAL), Spain; Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
4
Institute of Biomedical Research of Salamanca (IBSAL), Spain; Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León, Soria, Spain; Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Valladolid, Spain.
5
Institute of Biomedical Research of Salamanca (IBSAL), Spain; Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León, Soria, Spain; Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), Salamanca, Spain; Group of Biomedical Research in Critical Care Medicine (BioCritic), Valladolid, Spain. Electronic address: flopezher@usal.es.

Abstract

Nephrotoxicity is the main limitation to the dosage and anticancer efficacy of cisplatin. Cisplatin produces tubular epithelial cell apoptosis and necrosis depending on the concentration of the drug. Protection from cisplatin nephrotoxicity must therefore tackle both cell death modes. For its ability to reduce cisplatin reactivity, in addition to its antioxidant effect, we tested and found that N-acetylcysteine (NAC) was most effective at inhibiting cisplatin cytotoxicity. NAC has no significant effect on cell death induced by either cycloheximide or Fas activation, indicating a rather selective action. Pt-DNA-binding experiments suggest that the differential effectiveness of NAC is due to its capacity to quench cisplatin reactivity inside the cell. NAC abolishes cisplatin-induced apoptosis, and transforms the necrosis induced by high concentrations of cisplatin into apoptosis. In fact, NAC allows the anti-apoptotic molecule Bcl-2 to reduce the cell death caused by pro-necrotic concentrations of cisplatin, to a significantly greater extent than in the absence of NAC. In rats, a dosage of NAC that significantly ameliorates cisplatin nephrotoxicity, has little effect on gentamicin nephrotoxicity. These characteristics provide NAC with a rationale as a potential nephroprotectant specifically tailored to and especially effective for therapeutic courses with platinated antineoplastics, which prompts to deepening into further preclinical knowledge, and to initiate clinical studies with NAC and mixed therapies composed of NAC and antiapoptotic drugs.

KEYWORDS:

Apoptosis; Cisplatin; N-acetylcysteine; Necrosis; Nephroprotectant; Toxicity

PMID:
29679655
DOI:
10.1016/j.taap.2018.04.010
[Indexed for MEDLINE]

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