Effects of statins and farnesyltransferase inhibitors on proliferation and ERK phosphorylation in non-small lung cancer cells.

PURPOSE: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects independent of their lipid-lowering activity. Indeed, HMG-CoA reductase inhibition can affect post-translational processes, thus being responsible for decreased farnesylation and geranylgeranylation of intracellular small G proteins such as Ras, Rho and Rac, essential for cell survival and proliferation. In this regard, recent in vitro and in vivo studies suggest a possible role for both statins and farnesyltransferase inhibitors in the treatment of malignancies. METHODS: Within such a context, the aim of our study was to investigate the effects of either simvastatin (at concentrations of 1, 15, and 30 microM) or the farnesyltransferase inhibitor R115777 (at concentrations of 0.1, 1, and 10 microM) on primary cultures of non small lung cancer cells, including adenocarcinoma (GLC-82) and epidermoid (CALU-1) cell lines. In particular, we evaluated the actions of these two drugs on cell numbers and morphology, apoptosis, and phosphorylation of the ERK1/2 group of mitogen-activated protein kinases. Cell count was performed by Trypan blue staining, and Western blotting was used to detect ERK phosphorylation, as well as to assess apoptosis by evaluating caspase-3 expression. RESULTS: In both GLC-82 and CALU-1 lines, simvastatin and R115777 significantly reduced cell numbers and ERK phosphorylation; these effects, which reached the greatest intensity after 36 hours of treatment, were paralleled by a concomitant increase in caspase-3 cellular levels. CONCLUSION: Our results suggest that simvastatin and R11577 may exert, in susceptible lung cancer phenotypes, a pro-apoptotic and anti-proliferative activity, which appears to be mediated by inhibition of the Ras/Raf/MEK/ERK signaling pathway. CLINICAL IMPLICATIONS: Therefore, these preliminary findings may provide a rationale for evaluating the effects of statins and farnesyltransferase inhibitors in future clinical trials involving patients with lung cancer