SELECTIVE CYTOTOXICITY OF FARNESYLAMINE TO PANCREATIC-CARCINOMA CELLSAND KI-RAS-TRANSFORMED FIBROBLASTS

Farnesyl protein transferase (FPTase) catalyses the post-translational modification of proteins by a farnesyl pyrophosphate. One of the subs trates of this enzyme is p21(ras), the product of the ras oncogene. We examined whether farnesylamine, one of the FPTase inhibitors (FTI), i s selectively cytotoxic in pancreatic carcinoma cells and Ki-ras-trans formed fibroblasts. Furthermore, we investigated whether the cytotoxic ity of farnesylamine is caused by the induction of apoptosis in these cells. Using the FPTase assay, we found that farnesylamine inhibited F PTase in vitro. Immunoprecipitation showed that farnesylamine inhibite d farnesylation of p21(ras) in vivo. In addition, 24 and 5 mu M farnes ylamine were required to achieve 50% cytotoxicity in pancreatic carcin oma cells containing activated Ki-ras and Ki-ras-transformed NIH/3T3 c ells, respectively. The parental NIH/3T3 cells were resistant to the c ytotoxic effect of farnesylamine at concentrations less than 100 mu M. After incubation with farnesylamine, DNA fragmentation was observed i n both pancreatic carcinoma cells and Ki-ras-transformed fibroblasts a t cytotoxic doses of this compound but not in NIH/3T3 cells. These res ults indicate that the mechanism of cell death induced by farnesylamin e is apoptosis, and this apoptosis occurred specifically in pancreatic carcinoma cells containing mutated Ki-ras and the Ki-ras-transformed cells. Because raf is downstream of ras (p21(ras)) in the ras-raf-mito gen-activated protein kinase signaling pathway, we used c-raf-1-transf ormed fibroblasts, which proved to be resistant to apoptosis induced b y farnesylamine. This supports the theory that inhibition of ras signa ling may be related to the induction of apoptosis. These data further suggest that farnesylamine could be useful as a chemotherapeutic agent in cancers that very frequently contain a Ki-ras oncogene mutation, e .g., pancreatic cancer. (C) 1998 Wiley-Liss, Inc.