MECHANISM OF FARNESOL CYTOTOXICITY - FURTHER EVIDENCE FOR THE ROLE OFPKC-DEPENDENT SIGNAL-TRANSDUCTION IN FARNESOL-INDUCED APOPTOTIC CELL-DEATH

Mechanism of the inhibitory effect of isoprenoid farnesol on cell prol iferation has been studied in human acute leukemia CEM-C1 cells. Farne sol (20 mu M) reduced the rate of radioactive label incorporation into cellular diacylglycerol (DAG) and phosphocholine, the products of deg radation of phosphatidylcholine (PC), indicating inhibition of PC-spec ific phospholipase C after about 1 h of incubation. Inhibition of phos pholipase D by farnesol at the later incubation time (about 2 h) was d emonstrated by a decrease in synthesis of PC-derived phosphatidylethan ol in the presence of ethanol. These effects of farnesol on PC degrada tion and formation of DAG were followed by apoptotic fragmentation of cellular DNA and inhibition of cell growth. Exogenous DAG reduced the level of DNA fragmentation and cell growth inhibition. Results are con sistent with the involvement of cellular signal transduction in the me chanism of inhibition of cell proliferation by farnesol. (C) 1995 Acad emic Press. Inc.