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Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein

Tanja Peters1, Heike Lindenmaier, Walter E Haefeli

  • 1Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.

Naunyn-Schmiedeberg'S Archives of Pharmacology
|December 21, 2005
PubMed

Insights

Monastrol, an Eg5 inhibitor, shows weak interaction with P-glycoprotein (Pgp). This suggests potential for developing new cancer therapies that avoid multidrug resistance, unlike other antimicrotubule agents.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Monastrol is a small molecule inhibitor of Eg5, a motor protein crucial for mitotic spindle assembly.
  • Eg5 inhibitors offer potential for targeting cancer cells while minimizing neurotoxicity associated with other antimicrotubule drugs.
  • Multidrug resistance mediated by P-glycoprotein (Pgp) is a challenge for existing cancer therapies.

Purpose of the Study:

  • To investigate the interaction of monastrol with P-glycoprotein (Pgp) in vitro.
  • To determine if monastrol is a substrate or inhibitor of Pgp.
  • To assess the potential of monastrol and related Eg5 inhibitors in overcoming Pgp-mediated multidrug resistance.

Main Methods:

  • Calcein assay using P388/dx and porcine brain capillary endothelial cells.
  • Confocal laser-scanning microscopy with L-MDR1 cells.
  • Measurement of Pgp mRNA expression in LS180 cells.

Main Results:

  • Monastrol demonstrated weak inhibition of Pgp in vitro, with significantly higher f2 values compared to verapamil and quinidine.
  • Monastrol weakly induced Pgp mRNA expression, with a less potent effect than rifampicin.
  • Monastrol was not transported by Pgp, as evidenced by similar antiproliferative effects in Pgp-overexpressing and non-overexpressing cell lines.

Conclusions:

  • Monastrol exhibits minimal inhibitory and inductive effects on Pgp and is not a substrate for Pgp.
  • The weak interaction profile of monastrol with Pgp is promising for the development of novel Eg5 inhibitors.
  • Further research into Eg5 inhibitors may lead to effective cancer treatments that circumvent Pgp-mediated multidrug resistance.

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