title: Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice.
abstract: Cisplatin is an effective anticancer drug which has been used to treat a wide range of tumors for the last 30 years. However, its use is associated with nephrotoxicity. Protective strategies have been reported, but their impact on the antitumor activity of cisplatin has not been clarified. We have previously reported the protective potential of carvedilol against cisplatin nephrotoxicity in tumor-free rats. Therefore, in the present study we used a tumor-bearing model to investigate the impact of carvedilol on the antitumor activity of cisplatin. The renal damage induced by cisplatin and the protective effect of carvedilol were demonstrated by the levels of blood urea nitrogen and plasma creatinine as well as by renal histopathology and immunohistochemistry. The mechanism of protection was associated with significantly decreased (i) oxidative stress markers, (ii) Bax expression, (iii) caspase-3 activity and (iv) TUNEL labeling for apoptosis. More importantly, evaluation of tumor mass, tumor remission rate and the survival curve showed that carvedilol did not impair the antitumor action of cisplatin. These findings suggest that the mechanisms underlying the nephrotoxic and the antitumor activity of cisplatin might be different. This is the first study to report such findings. Compared to other reported potential cytoprotectors against cisplatin-induced nephrotoxicity, carvedilol stands out due to the fact that it is already clinically-employed and well tolerated by the patients. Based on these features and on the present findings, carvedilol is a very promising candidate for future clinical trials as nephroprotector in patients treated with cisplatin.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av. do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Carvalho Rodrigues
authors.forename: Marcia C da
authors.initials: MC
authors.lastname: Silva Faria
authors.forename: Neife A G dos
authors.initials: NA
authors.lastname: Santos
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
authors.forename: Antonio Cardozo
authors.initials: AC
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D000077261:Carvedilol; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D002945:Cisplatin
keywords: Carvedilol; Cisplatin; Kidneys; Nephrotoxicity; Sarcoma-180