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Updated: Jul 25, 2026
Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice
Published on: October 27, 2014
A comparison of signaling activities induced by Taxol and desoxyepothilone B
D T Bergstralh1, D J Taxman, T C Chou
1Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
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 signaling, 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 correlated 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 pathways, and the increased efficacy of dEpoB in resistant tumor lines lies in differential susceptibility to P-gp.
Insights
Desoxyepothilone B (dEpoB) shows efficacy in Taxol-resistant tumors. This study reveals that P-glycoprotein (P-gp) expression, not ERK signaling, dictates differential sensitivity to these microtubule inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Desoxyepothilone B (dEpoB) is a novel microtubule inhibitor in clinical trials.
- dEpoB exhibits a similar mechanism of action to paclitaxel (Taxol).
- dEpoB demonstrates efficacy in some Taxol-refractory cell lines and tumor xenografts.
Purpose of the Study:
- To compare the signaling pathways induced by dEpoB and Taxol.
- To identify the molecular basis for dEpoB's enhanced efficacy in resistant cell lines.
- To investigate the role of ERK signaling and P-glycoprotein (P-gp) in differential drug sensitivity.
Main Methods:
- Affymetrix gene expression analysis was performed.
- MEK inhibitor was used in combination with dEpoB and Taxol.
- Differential sensitivity was assessed in Taxol-resistant cell lines.
- The role of P-glycoprotein (P-gp) was directly demonstrated.
Main Results:
- Both dEpoB and Taxol activate similar G2-blocking pathways, including ERK signaling.
- ERK signaling did not play a role in the differential sensitivity observed.
- Gene modulation patterns were similar between dEpoB and Taxol treatments.
- Differential sensitivity in Taxol-resistant lines strongly correlated with P-glycoprotein (P-gp) expression.
Conclusions:
- Taxol and dEpoB induce comparable cell death pathways.
- The increased efficacy of dEpoB in Taxol-resistant tumors is attributed to differential susceptibility to P-gp.
- P-gp expression is a key determinant of resistance to both Taxol and dEpoB.
