Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. FASEB J 2013 Aug;27(8):2946-56
Date
04/23/2013Pubmed ID
23603837Pubmed Central ID
PMC3714587DOI
10.1096/fj.12-218040Scopus ID
2-s2.0-84881128520 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.
Author List
Khan MA, Liu J, Kumar G, Skapek SX, Falck JR, Imig JDMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAdministration, Oral
Animals
Apoptosis
Blood Urea Nitrogen
Cell Line, Tumor
Cell Survival
Cisplatin
Creatinine
Cross-Linking Reagents
Dose-Response Relationship, Drug
Endoplasmic Reticulum Stress
Gene Expression
HEK293 Cells
HeLa Cells
Humans
Kidney
Kidney Diseases
Male
Proto-Oncogene Proteins c-bcl-2
Rats
Rats, Inbred WKY
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase
Superoxide Dismutase-1
Vasodilator Agents
