Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice

• Published in: Chemico-biological interactions Vol. 206; no. 1; pp. 90 - 99
• Main Authors: Carvalho Rodrigues, Maria A., Silva Faria, Marcia C. da, Santos, Neife A.G. dos, Gobe, Glenda C., dos Santos, Antonio Cardozo
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25-10-2013
• Subjects: Animals; anticarcinogenic activity; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; blood; Carbazoles - chemistry; Carbazoles - pharmacology; Carvedilol; caspase-3; Cisplatin; Cisplatin - administration & dosage; Cisplatin - chemistry; Cisplatin - pharmacology; clinical trials; creatinine; Dose-Response Relationship, Drug; histopathology; immunohistochemistry; Kidney - drug effects; Kidney - metabolism; Kidneys; Male; Mice; Molecular Structure; neoplasms; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Nephrotoxicity; oxidative stress; Oxidative Stress - drug effects; patients; Propanolamines - chemistry; Propanolamines - pharmacology; protective effect; rats; remission; Sarcoma-180; Structure-Activity Relationship; survival rate; urea nitrogen; Xenograft Model Antitumor Assays; Kidneys; Nephrotoxicity; Carvedilol; Cisplatin; Sarcoma-180
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2013.08.015

•Carvedilol protects against the nephrotoxicity of cisplatin in tumor-bearing mice.•Carvedilol does not affect the antitumor activity of cisplatin.•The protection involves inhibition of oxidative stress and apoptosis in kidneys.•The antitumor and nephrotoxic mechanisms of cisplatin might be different.•This is the first study to report such findings.
Cisplatin is an effective anticancer drug which has been used to treat a wide range of tumors for the last 30years. 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.