Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin.

Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.

Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice.

Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.

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

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.