Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells

beta-Hydroxy-beta-methylglutaryl coA reductase inhibitors (HRIs) inhibit is oprenylation of several members of the Ras superfamily of proteins and ther efore have important cellular effects, including the reduction of prolifera tion and increasing apoptosis, Significant toxicity at high doses has precl uded the use of HRIs as a monotherapy for cancers, We therefore studied whe ther combinations of the HRI lovastatin with standard chemotherapeutic agen ts would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with diff ering sensitivity. Pretreatment with lovastatin significantly increased apo ptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines . Lovastatin treatment resulted in decreased expression of the anti-apoptot ic protein bcl-2 and increased the expression of the proapoptotic protein b ar. The addition of geranylgeranylpyrophospate (10 mu M) prevented lovastat in-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 mu M) was partially effective, whereas cotreatment with farnesyl pyro phosphate (100 mu M) had no effect. These data imply that lovastatin acts b y 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.