Effects of farnesyltransferase inhibitors on cell cycle progression of human cancer cells

Abstract

Farnesyltransferase inhibitors (FTIs) represent a novel class of anti-cancer drugs with preferential effects on transformed cells. FTIs are currently evaluated in clinical trials. They are developed with the idea to inhibit farnesylation and membrane association of proteins such as Ras. In support of this idea, FTIs are effective in interfering with phenotypes due to H-ras activation, although K-ras activated events are resistant to FTIs. Recent studies on farnesylated proteins also raised the possibility that FTIs affect farnesylated proteins other than H-ras. To gain insight into this possibility, we have examined cellular effects of FTIs on human cancer cells. We, as well as others, have observed that FTIs cause enrichment of G0/G1-phase cells with a number of cancer cells. In addition, FTIs affect proteins involved in cell cycle regulation, such as retinoblastoma protein, p21^Waf1/Cip1 and cyclins. With some cancer cell lines, FTI causes G2/M enrichment. Proteins, such as farnesylated Rho proteins and centromere binding proteins CENP-E/F may play roles in these cell cycle effects.