3‐hydroxy‐3‐methylglutaryl‐coenzyme A ( HMG‐CoA) reductase inhibitors (statins) 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 farnesyl transferase inhibitors in the treatment of malignancies. Within such a context, the aim of our study was to investigate effects of either simvastatin (at concentrations of 1, 15, and 30 μ m) or the farnesyl transferase inhibitor R115777 (at concentrations of 0.1, 1, and 10 μ m), on two cultures of human non‐small lung cancer cells, adenocarcinoma ( GLC‐82) and squamous ( CALU‐1) cell lines. In particular, we evaluated actions of these two drugs on phosphorylation of the ERK1/2 group of mitogen‐activated protein kinases and on apoptosis, plus on cell numbers and morphology.
Western blotting was used to detect ERK phosphorylation, and to assess apoptosis by evaluating caspase‐3 activation; apoptosis was also further assessed by terminal deoxynucleotidyl‐mediated d UTP nick end labelling ( TUNEL) assay. Cell counting was performed after trypan blue staining.
In both GLC‐82 and CALU‐1 cell lines, simvastatin and R115777 significantly reduced ERK phosphorylation; this effect, which reached the greatest intensity after 36 h treatment, was paralleled by a concomitant induction of apoptosis, documented by significant increase in both caspase‐3 activation and TUNEL‐positive cells, associated with a reduction in cell numbers. Our results thus suggest that simvastatin and R115777 may exert, in susceptible lung cancer cell phenotypes, a pro‐apoptotic and anti‐proliferative activity, which appears to be mediated by inhibition of the Ras/Raf/ MEK/ ERK signalling cascade.