Abstract
Even though farnesyltransferase inhibitors (FTIs), a novel class of therapeutic agents presently in clinical trials, have preclinically outstanding anticancer activity and impressive lack of toxicity, their mechanism of action is not well understood. To enhance our understanding of how FTIs inhibit the growth of tumors, we have investigated their effects on cell cycle progression of two human lung cancer cell lines, A-549 and Calu-1. In this report, we show in synchronized A-549 and Calu-1 cells that FTI-2153 treatment resulted in a large accumulation of cells in the mitosis phase of the cell division cycle, with some cells in the G(0)/G(1) phase. Furthermore, microtubule immunostaining and 4,6-diamidino-2-phenylindole DNA staining demonstrated that the FTI-2153-induced accumulation in mitosis is due to the inability of these cells to progress from prophase to metaphase. FTI-2153 inhibited 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-shaped chromosome morphology and inhibited chromosome alignment. Time-lapse videomicroscopy 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 centromeric 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.
Highlights
Even though farnesyltransferase inhibitors (FTIs), a novel class of therapeutic agents presently in clinical trials, have preclinically outstanding anticancer activity and impressive lack of toxicity, their mechanism of action is not well understood
To enhance our understanding of how FTIs inhibit the growth of tumors, we have investigated their effects on cell cycle progression of two human lung cancer cell lines, A-549 and Calu-1
To determine the effects of inhibition of protein farnesylation on cell cycle progression, we have used a standard method to synchronize cells (18). This was accomplished by blocking cells in G1 by treatment with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin for 48 h and releasing the block by supplying mevalonic acid (MVA), the product of the reaction catalyzed by 3-hydroxy-3methylglutaryl-coenzyme A reductase
Summary
Even though farnesyltransferase inhibitors (FTIs), a novel class of therapeutic agents presently in clinical trials, have preclinically outstanding anticancer activity and impressive lack of toxicity, their mechanism of action is not well understood. The interest in farnesyltransferase was heightened when it was discovered that Ras requires farnesylation for its cancer-causing activity This prompted many researchers to design farnesyltransferase inhibitors (FTIs) as potential anticancer drugs (6 – 8). Some of the FTIs were shown to inhibit potently farnesyltransferase in vitro (IC50 in the picomolar range) and in whole cells (nanomolar range), to antagonize oncogenic HRas signaling, and to induce apoptosis in Ras-transformed fibroblasts when deprived of either serum or substratum attachment. FTIs have been shown to be potent inhibitors of tumor growth in several animal models Their impressive antitumor activity and lack of toxicity to normal cells have led to ongoing human clinical trials with several FTIs (10). To date, the critical target for FTIs has not been identified
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