Insights into the mevalonate pathway in the anticancer effect of a platinum complex on human gastric cancer cells.

A platinum(II) complex [Pt(en)]ZL [en = ethylenediamine; ZL = 1-hydroxy-3(1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly called as zoledronic acid] has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. It exhibited cytotoxic effects on the human cancer cells SGC7901, HepG2, MCF-7, MDA-MB-231, HCT116, and U2OS, and the cytotoxicity against SGC7901 is particularly remarkable. It also showed higher cytotoxicity and better selectivity than the corresponding ligand ZL in inhibiting cancer cells SGC7901 and HepG2 rather than normal cells GES-1 and LO2. To investigate the role of mevalonate pathway involved in the mechanism of anticancer action of [Pt(en)]ZL, the effects of farnesol (FOH) and geranylgeraniol (GGOH), precursors of important mevalonate pathway intermediates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), on the cytotoxic effects of [Pt(en)]ZL against the human gastric cancer cells SGC7901 were investigated systematically, since inhibition of the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway was acknowledged as the mechanism of most anticancer actions of the ligand ZL. The experiments revealed that FOH and GGOH both rescued the SGC7901 cells, especially FOH. The cell cycle arrest and apoptosis of SGC7901 cells induced by [Pt(en)]ZL was decreased by the addition of FOH, and the prenylation of small guanine-nucleotide-binding regulatory proteins (small G proteins) down-regulated by [Pt(en)]ZL was recovered by the addition of FOH, demonstrating that [Pt(en)]ZL exerted anticancer effects on SGC7901 via inhibiting the mevalonate pathway. This will provide deep insights into the mechanism of action of [Pt(en)]ZL.