Delayed tumor development induced by lovastatin, an inhibitor of cholesterol synthesis, in mice bearing a highly aggresive mammary carcinoma

ALONSO, D.F; FARINA, H.G; SKILTON, G; GABRI, M.R; DE LORENZO, M.S; GÓMEZ DE

New Orleans, LA, EEUU

Congreso; 89st Annual Meeting, American Association for Cancer Research (AACR); 1998

American Association for Cancer Research (AACR)

Lovastatin, a fungal antibiotic used in the treatment of hypercholesterolemia, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the key regulatory enzyme in the mevalonate pathway of cholesterol synthesis. We examined the antitumor properties of lovastatin on the F3II sarcomatoid mammary carcinoma, a highly invasive and metastatic murine tumor model.  Female BALB/c inbred mice were inoculated subcutaneously with F3II tumor cells and injected i.p. daily with 10 mg/kg body weight of lovastatin or administered p.o. at a level corresponding to the human dosage of 1-2 mg/kg/day. Treatment inhibited tumor formation, prolonged tumor latency, and reduced the metastatic dissemination to lungs of established mammary tumors. In vitro, antitumor properties of lovastatin were strongly associated with inhibition of tumor cell attachment and migration. These actions were prevented by addition of mevalonate but not by equivalent concentrations of farnesyl pyrophosphate. In accordance, Western blot assays showed that lovastatin effects did not appear to be related to modifications in Ras oncoproteins in our model. The present data indicate that lovastatin could be an antitumor agent with potentially useful clinical applications in breast cancer.