Cerivastatin enhances the cytotoxicity of 5-fluorouracil on chemosensitive and resistant colorectal cancer cell lines.
Cerivastatin is one of the synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors used for the treatment and prevention of hypercholesterolaemia. The observation that patients receiving this drug had a lower incidence at cancer led to our interest in using it as a putative anticancer agent. In this study, we tested the cytotoxicity of cerivastatin on a panel of 5-fluorouracil (5FU) sensitive and resistant cell lines in vitro. Cerivastatin was cytotoxic to both 5FU sensitive and resistant cells. Cerivastatin significantly augmented the cytotoxic effect of 5FU on drug sensitive (6-22-fold) and resistant (229-310-fold) cell lines. Cerivastatin and 5FU acted synergistically. Cerivastatin inhibited nuclear factor kappaB DNA binding activity. The enhancing effect of cerivastatin on 5FU was partially mevalonate pathway independent. Cerivastatin may allow successful 5FU therapy in chemoresistant patients.
Wang
Weiguang
W
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, UK. w.wang@beatson.gla.ac.uk
Collie-Duguid
Elaina
E
Cassidy
James
J
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000473:pathology*; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D005472:Fluorouracil / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D004247:DNA; C086276:cerivastatin; D008798:Mevalonic Acid; D005472:Fluorouracil