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Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine

Brian T Castle1, Seth McCubbin2, Louis S Prahl1

  • 1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455.

Molecular Biology of the Cell
|March 17, 2017
PubMed

Insights

Microtubule-targeting agents (MTAs) stabilize microtubules through two distinct mechanisms. This research clarifies how MTAs like paclitaxel and vinblastine affect microtubule dynamics, crucial for cancer drug development.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • Microtubule-targeting agents (MTAs) are vital chemotherapeutics and biological probes.
  • MTAs function by binding tubulin and kinetically stabilizing microtubules, inhibiting dynamic instability.
  • The precise molecular mechanisms and thermodynamic/kinetic underpinnings of MTA-induced kinetic stabilization remain incompletely understood.

Purpose of the Study:

  • To elucidate the kinetic and thermodynamic basis of kinetic stabilization induced by paclitaxel and vinblastine.
  • To differentiate the mechanisms of kinetic stabilization employed by assembly-promoting (paclitaxel) and disassembly-promoting (vinblastine) MTAs.
  • To define the fundamental requirements for microtubule dynamic instability and its suppression by MTAs.

Main Methods:

  • Integration of a computational model for microtubule assembly.
  • Application of nanometer-scale fluorescence microscopy in live cells.
  • Analysis of kinetic and thermodynamic parameters governing tubulin dynamics.

Main Results:

  • Identified two distinct modes of kinetic stabilization by MTAs in live cells.
  • Vinblastine exhibits true kinetic stabilization by suppressing on-off kinetics.
  • Paclitaxel demonstrates "pseudo" kinetic stabilization by reducing the GTP- and GDP-tubulin energy difference.
  • Both MTAs effectively stabilize microtubules against disassembly, particularly without a GTP cap.

Conclusions:

  • The study clarifies the distinct molecular mechanisms underlying kinetic stabilization by different classes of MTAs.
  • Understanding these mechanisms provides insight into microtubule dynamics and MTA efficacy.
  • Findings contribute to the rational design of novel chemotherapeutic agents targeting microtubule dynamics.

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