Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells.
Beta-hydroxy-beta-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 microM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 microM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 microM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.
Agarwal
B
B
Department of Medicine, St. Luke's-Roosevelt Hospital Center, New York, New York 10025, USA.
Bhendwal
S
S
Halmos
B
B
Moss
S F
SF
Ramey
W G
WG
Holt
P R
PR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D008854:Microscopy, Electron; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012717:Sesquiterpenes; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D051028:bcl-2-Associated X Protein; C004808:farnesyl pyrophosphate; D008148:Lovastatin; C002963:geranylgeranyl pyrophosphate; D002945:Cisplatin; D008798:Mevalonic Acid; D005472:Fluorouracil