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

Abstract

Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC 50 : 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 apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize 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, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxelinduced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth 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 epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

“…42 High levels of plasminogen activators as well as MMP-2 and MMP-9 have been correlated with aggressive phenotypes in different cancers, including prostate 27 and renal 43 cancers. Since Ras plays critical roles in multiple signaling pathways, inhibition of its farnesylation by SCH-66336, as observed for H-Ras in PC-3 and Caki-1 cells and as reported for the FTI L-744,842 in another prostate cancer cell line, 44 should reduce transcription and/or secretion of gelatinases and plasminogen activators. This conclusion is based on multiple observations.…”

Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone

“…Some epothilones exhibit enhanced cytotoxicity against P-gp-overexpressing tumor cells, compared with paclitaxel (13)(14)(15), and certain epothilone derivatives are poorly recognized by P-gp pumps (16,17). This suggests that some epothilones may overcome multidrug resistance (MDR) mechanisms, which would augment their therapeutic potential.…”

Highlights of Natural Products in Prostate Cancer Drug Discovery

“…The progress of epothilones in the PC setting has been extensively reviewed (Lee & Kelly, 2009, Lassi & Dawson, 2010, Cheng et al, 2008, Bystricky & Chau, 2011. Patupilone inhibits the proliferation of DU145 and TSU-Pr1 PC cells in the low nanomolar range causing mitotic arrest (Sepp-Lorenzino et al, 1999). Inhibition of proliferation appears to be dependent on the p53 status of the tumor cells (Ioffe et al, 2004).…”