The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells

Even though farnesyltransferase inhibitors (FTIs), a novel class of therape utic agents presently in clinical trials, have preclinically outstanding an ticancer activity and impressive lack of toxicity, their mechanism of actio n is not well understood. To enhance our understanding of how FTIs inhibit the growth of tumors, we have investigated their effects on eel cycle progr ession of two human lung cancer cell lines, A-549 and Calu-1. In this repor t, we show in synchronized A-549 and Calu-1 cells that FTI-2153 treatment r esulted in a large accumulation of cells in the mitosis phase of the cell d ivision cycle, with some cells in the G(0)/G(1) phase. Furthermore, microtu bule immunostaining and 4,6-diamidino-2-phenylindole DNA staining demonstra ted that the FTI-2153-induced accumulation in mitosis is due to the inabili ty of these cells to progress from prophase to metaphase. FTI-2153 inhibite d the ability of A-549 and Calu-1 cells to form bipolar spindles and caused formation of monoasteral spindles. Furthermore, FTI-2153 induced a ring-sh aped chromosome morphology and inhibited chromosome alignment. Time-lapse v ideomicroscopy confirmed this result by showing that FTI-2153-treated cells are unable to align their chromosomes at the metaphase plate. FTI-2153 did not affect the localization to the kinetochores of two farnesylated centro meric proteins, CENP-E and CENP-F. Thus, a mechanism by which FTIs inhibit progression through mitosis and tumor growth is by blocking bipolar spindle formation and chromosome alignment.