Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells

Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer d rugs that show promise in blocking the growth of tumors. Here, we report th at FTIs are capable of inducing apoptosis of transformed but not untransfor med cells, Treatment of v-K-ras-transformed normal rat kidney (KNRK) cells with FTIs leads to the induction of apoptotic cell morphology, chromatin co ndensation and DNA fragmentation. In addition, fluorescence-activated cell sorter analysis of FTI-treated KNRK, cells shows a sub-G(1) apoptotic peak (chromosome content of <2 N), This FIT-induced apoptosis is evident only wh en the cells are grown in low serum conditions (0.1% fetal calf serum) and is observed selectively with transformed KNRK cells and not with untransfor med NRK cells. Further analysis of the mechanism underlying this apoptosis has shown that FTI treatment of KNRK cells results in the activation of cas pase 3 but not caspase I, Moreover, the addition of Z-DEVD-fmk, an agent th at interferes with caspase 3 activity, can inhibit FTI-induced apoptosis in a dose-dependent manner. Introduction of the CASP-3 gene into MCF7 cells, which lack caspase 3 activity, results in a significant increase of FTI-ind uced apoptosis, Furthermore, FTI induces the release of cytochrome c into t he cytosol, This release is an important feature of caspase 3-mediated apop tosis, These results suggest that FTIs induce apoptosis through the release of cytochrome c from the mitochondria resulting in caspase 3 activation.