Cytotoxicity of Simvastatin to Pancreatic Adenocarcinoma Cells Containing Mutant ras Gene

Simvastatin (SV), a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, inhibits the synthesis of mevalonic acid. The dose‐dependent (0.1–100 μg/ml) cytotoxicity of SV towards human (MIAPaCa‐2, Panc‐1, HPC‐1, HPC‐3, HPC‐4, PK‐1, PK‐9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. At up to 20 μg/ml of SV, the effect was reversible and was restored by 60 μg/ml mevalonic acid. Point mutation of Ki‐ras at codon 12 in each cell line was detected by means of the modified polymerase chain reaction. The concentration of SV necessary to achieve 50% cytotoxicity was about 10 μg/ml, and at this concentration of SV, DNA synthesis assayed in terms of [(3)H]thymidine uptake, isoprenylation of p21(ras) examined by Western blotting and cell progression from G1 to S phase of the cell cycle analyzed by flow cytometry were all inhibited. Isoprenylation inhibitors of p21(ras), such as SV, are expected to be useful for the treatment of pancreatic cancer.