Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.

Anti-tumor effects and cellular mechanisms of resveratrol

“…In the DENA induced HCC model in SD rats, a 20-week administration of resveratrol (50, 100, 300 mg/kg) was shown to inhibit hepatocyte nodules in a dose-dependent manner (85) through the down-regulation of HSP70 and COX-2 expression by attenuating the translocation of NF-κB from the cytoplasm to the nucleus. In another study with the same administered dose of resveratrol, it was also found that the level and expression of hepatic TNF-α, IL-1β and IL-6 induced by DENA was reversed (86,87). Thus resveratrol mediated an anti-tumor effect of rat liver tumor via alteration of proinflammatory cytokines.…”

Fabrication, optimization, and characterization of umbelliferone β-D-galactopyranoside-loaded PLGA nanoparticles in treatment of hepatocellular carcinoma: in vitro and in vivo studies

“…The restoration of these enzymes is also attributed to our formulation. [24][25][26][27][28] Histological studies reveal that the HCC expansion occurs in the backdrop of chronic inflammation and NF-κB is the chief mediator of inflammation, regulating other inflammatory molecules either downstream or upstream. 18,23,29 Liver is the production center for synthesis of cytokines such as TNF-α, IL-1β, and IL-6 by blood cells (monocytes and lymphocytes).…”

Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male Wistar rats

“…Many studies have highlighted the chemopreventive potential of resveratrol in experimental hepatocarcinogenesis in rodent models (12,18,19). Bishayee and Dhir (12) demonstrated the chemopreventive effects of resveratrol in DEN-induced hepatocarcinogenesis in female Sprague Dawley rats.…”