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

Epothilones are a new class of natural products that bind to tubulin and pr event the depolymerization of microtubules, although they have no structura l similarity to paclitaxel. Taxanes are only marginally effective in the tr eatment of disseminated prostate cancer, although they may have useful acti vity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multid rug resistant cells. Epothilones A and B (EA, EB) have recently been synthe sized ii tote. In this report, we examine the effects of synthetic epothilo nes and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (I C50: 50 - 75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptoti c cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, sta bilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, w e showed that farnesyl transferase inhibitors sensitize tumor cells to pacl itaxel-induced mitotic arrest. We now have extended these observations to s how that paclitaxel and the epothilones synergize with FTI to arrest the gr owth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and e pothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.