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 micrograms/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 micrograms/ml of SV, the effect was reversible and was restored by 60 micrograms/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 micrograms/ml, and at this concentration of SV, DNA synthesis assayed in terms of [3H]thymidine uptake, isoprenylation of p21ras 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 p21ras, such as SV, are expected to be useful for the treatment of pancreatic cancer.
Ura
H
H
Third Department of Internal Medicine, Asahikawa Medical College, Hokkaido.
Obara
T
T
Nishino
N
N
Tanno
S
S
Okamura
K
K
Namiki
M
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D003062:Codon; D006224:Cricetinae; D004273:DNA, Neoplasm / Q000096:biosynthesis; D011905:Genes, ras; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000633:toxicity; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D017368:Protein Prenylation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012680:Sensitivity and Specificity; D019821:Simvastatin; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003062:Codon; D004273:DNA, Neoplasm; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)