Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Abstract

Summary The effect of pravastatin, an inhibitor of p21 ras isoprenylation, on hepatocarcinogenesis induced by N-nitrosomorpholine and on p2l s isoprenylation were investigated in male Sprague-Dawley rats. Rats received i.p. injections of pravastatin (10 and 20 mg kg-1 body weight) every other day and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Vesible white nodules and hepatic lesions staining positively for gamma-glutamyl transpeptidase or glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 15, pravastatin at both dosages significantly reduced the incidence, number and volume of visible white nodules. Quantitative histological analysis also showed that prolonged administration of pravastatin at both dosages resulted in significant reductions in the number and percentage area of hepatic lesions positive for gamma-glutamyl transpeptidase and glutathione-S-transferase, placental type. Administration of pravastatin also significantly decreased the amount of membrane-associated p21 ras in the tumour and the labelling index of neoplastic nodules and increased the apoptoic indices of neoplastic nodules. These findings indicate that pravastatin suppresses hepatocarcinogenesis and suggest that this effect might be related to pravastatin's inhibition of p21 ras isoprenylation and its subsequent inhibition of cell proliferation and induction of apoptosis in neoplastic lesions.

Chemoembolization Combined with Pravastatin Improves Survival in Patients with Hepatocellular Carcinoma

“…Several preclinical trials confirm an anticancer efficacy of statins, investigating the mechanisms leading to growth inhibition [36]. In a recent study, Sutter et al [22] showed that HMG-CoAR inhibitors decreased the proliferation of HCC cells by inducing apoptosis and cell cycle arrest.…”

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

“…In 1,2-dimethylhydrazine-induced colon car- cinogenesis in ICR mice, simvastatin and pravastatin significantly reduced tumor frequency (Narisawa et al 1994). Pravastatin has been shown to reduce the incidence and volume of N-nitrosomorpholine-induced rat hepatic neoplastic nodules (Tatsuta et al 1998) and NMU-induced rat colon carcinogenesis (Narisawa et al P. Kubatka et al 1996). Moreover, several studies in rodents have also shown preventive effects of lipophilic statins on the growth of diverse tumors (Hawk et al 1996;Inano et al 1997;Kikuchi et al 1997;Matar et al 1998).…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…High doses of lovastatin (500 mg/kg day), but not doses lower than 180 mg/kg day, induced an increased incidence of hepatocellular and pulmonary cancer in animal models (MacDonald et al, 1988); in rodents, fluvastatin was found to be associated with thyroid cancer and forestomach papillomas (Robison et al, 1994). On the other hand, in mice and rats, the chemically induced colon carcinogenicity was reduced by both simvastatin and pravastatin (Narisawa et al, 1994;Narisawa et al, 1996), and pravastatin also decreased the number and volume of N-nitrosomorpholine-induced hepatic neoplastic nodules (Tatsuta et al, 1998).…”