A Comparison of Signaling Activities Induced by Taxol and Desoxyepothilone B

Abstract

Desoxyepothilone B (dEpoB), currently in clinical trials, is a novel microtubule inhibitor with similar mode-of-action to paclitaxel (Taxol). Intriguingly, it is effective in some cell lines and tumor xenografts refractory to Taxol. The purpose of this study is to compare signaling induced by the two drugs and identify a molecular basis for increased efficacy of dEpoB in resistant lines. The importance of ERK sig-naling, already established for Taxol, was shown for dEpoB and other G2-blocking agents. However, a role in differential sensitivity was not observed. Affymetrix analysis shows similar gene modulation by either agent, alone or in combination with MEK inhibitor. Differential sensitivity in a set of Taxol-resistant lines correlat-ed to the expression of P-glycoprotein (P-gp), and its importance was demonstrated directly. These results suggest that Taxol and dEpoB elicit similar cell death path-ways, and the increased efficacy of dEpoB in resistant tumor lines lies in differen-tial susceptibility to P-gp.

Keywords:

• dEpoB
• MEK
• Taxol
• P-gp
• MDR