Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones

Abstract

An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. Specific farnesyl transferase inhibitors (FTIs) have been developed that selectively inhibit the processing of these proteins. FTIs have been shown to be potent inhibitors of tumor cell growth in cell culture and in murine models and at doses that cause little toxicity to the animal. These data suggest that these drugs might be useful therapeutic agents. We now report that, when FTI is combined with some cytotoxic antineoplastic drugs, the effects on tumor cells are additive. No interference is noted. Furthermore, FTI and agents that prevent microtubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth. FTI causes increased sensitivity to induction of metaphase block by these agents, suggesting that a farnesylated protein may regulate the mitotic check point. The findings imply that FTI may be a useful agent for the treatment of tumors with wild-type ras that are sensitive to taxanes.Potent and specific peptidomimetic inhibitors of farnesyl transferase (FTIs) have been synthesized and characterized by several laboratories (1-4). These compounds originally were conceived as potential anti-neoplastic drugs because the Ras family of proteins is farnesylated. Members of the ras family of protooncogenes are mutated in 30% of human cancers, and the Ras protein plays an important role in the development and progression of many human cancers. Ras is isoprenylated through the addition of a C15 farnesyl moiety. This modification confers association with the plasma membrane. Mutants of Ras that do not become membrane-associated are not transforming, and FTIs cause the reversion of transformation of fibroblasts that express the Ha-ras gene (reviewed in ref. 5).FTIs also inhibit the growth of a majority of human tumor cells in culture. In a variety of animal systems, including v-H-ras transgenic mice and xenograft models, FTIs inhibit tumor growth, causing complete tumor regression in some murine models (6, 7). However, it is not clear that the key defarnesylated target protein is Ras. Human tumor cells without ras mutation often are quite sensitive to FTIs (8). The membrane association of Ki-ras and N-ras proteins is much less sensitive than is that of Ha-ras, yet tumor cells containing mutated Ki-ras can be quite sensitive to the drug (7, 9). Remarkably, even though FTI affects the processing of wildtype Ras protein, the drug has little discernible toxicity in animals at doses that have major anti-tumor effects (6).These data do not rule out the possibility that Ras inhibition plays an important role in FTI action, but they suggest that other targets may be involved (10). A number of other proteins are known to be farnesylated, including RhoB and Rap2, lamins A and B, phosphorylase kinase, rhodopsin kinase, cyclic GMP phosphodiesterase, and the ␥ subunit of transducin (5). Whatever the mecha...

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

“…40 As these drugs are generally non-toxic, we went on to test whether they would be effective when given in combination with traditional cytotoxic drugs. We found that farnesyl transferase inhibitors sensitized cells to the mitotic block induced by paclitaxel and, in combination, the two drugs cause synergistic arrest of cell growth and apoptosis , 41,42 in this report we extend these observations. Epothilones or paclitaxel in combination with farnesyl transferase inhibitors display marked synergy in inhibiting the growth of the prostate cell line DU145 (Figure 8).…”

Paclitaxel-induced cell death

“…FTI increases cell sensitivity to induction of the G 2 /M block by paclitaxel, suggesting that a farnesylated protein may regulate the mitotic checkpoint. 117 6) A macrocyclic lactone protein kinase C (PKC) activator, bryostatin 1, has been shown to enhance paclitaxel-induced apoptosis of leukemia cells. 118 7) An inhibitor of phosphatidylinositol synthesis, inostamycin, reduces the dosage of paclitaxel required for apoptosis induction in lung carcinoma cells.…”

Targeting Aberrant Signal Transduction Pathways in Lung Cancer

“…Despite the fact that FTIs cause the phenotypic reversion of Ras-mediated transformation in vitro, these effects seem to be reversible and do not require mutant Ras for activity. [58][59][60] Still, the efficacy of FTIs is improved in combination with cytotoxic chemotherapeutic agents, 59,[61][62][63] and some studies suggest FTIs act synergistically in combination with cytotoxic agents in human lung cancer, which is discussed below.…”