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Cancer Chemotherapy and Pharmacology

Published in:

01-07-2017 | Original Article

Possible involvement of the lipoxygenase and leukotriene signaling pathways in cisplatin-mediated renal toxicity

Authors: Osama A. Alkhamees, Abdulaziz S. Alroujayee, Hatem M. Abuohashish, Fatima S. Alrojayee, Mohammed M. Ahmed

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2017

Abstract

Purpose

The present study examined the possible involvement of the lipoxygenase (LOX) pathway in cisplatin (CPT)-induced nephrotoxicity.

Methods

Wistar albino rats were challenged with CPT IP injection (7.5 mg/kg) and were sacrificed after one week. Signs of renal dysfunction, including urea and creatinine clearance levels and renal histological structure, were investigated. Gene and protein expression levels of different LOX pathway enzymes and products, including 5-LOX, 12-LOX, 15-LOX, 5-LOX activating protein (FLAP), leukotriene A4 hydrolase (LTA4 hydrolase), leukotriene C4 synthase (LTC4 synthase), LTB4 receptor, and cysteinyl (cys) LT receptor types 1 and 2, were also determined in the kidneys using real-time PCR and western blotting, respectively. The serum and kidney levels of LTB4 and inflammatory markers were also estimated.

Results

CPT renal toxicity was established as the creatinine and urea clearance levels were significantly reduced, while the serum levels of creatinine and urea were markedly increased. We reported a considerable up-regulation in the mRNA and protein expression levels of 5-LOX, FLAP, 12-LOX, LTA4 hydrolase, LTC4 synthase, LTB4 receptor, and Cys LT receptor types 1 and 2, while 15-LOX expression did not significantly change in the CPT group. Additionally, LTB4 and inflammatory indicators in serum and renal levels were elevated significantly in the CPT group. Histopathological examination clearly showed the nephrotoxic changes in the renal tissues of CPT-challenged animals.

Conclusions

Our findings suggested, for the first time, the participation of LOX enzymes and products in the signaling pathway leading to CPT-associated nephrotoxicity, which could be the foundation stone for combining LOX pathway attenuators with CPT therapy to decrease CPT-associated renal toxicity.

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Title: Possible involvement of the lipoxygenase and leukotriene signaling pathways in cisplatin-mediated renal toxicity
Authors: Osama A. Alkhamees
Abdulaziz S. Alroujayee
Hatem M. Abuohashish
Fatima S. Alrojayee
Mohammed M. Ahmed
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2017
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3331-8

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