Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4105-10. doi: 10.1073/pnas.1015181108. Epub 2011 Feb 22.

Abstract

Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca(2+) mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca(2+) and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca(2+) concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.

MeSH terms

  • Benzoquinones / metabolism
  • Benzoquinones / pharmacology
  • Cell Line, Tumor
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / metabolism
  • Lactams, Macrocyclic / pharmacology
  • Micelles
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Voltage-Dependent Anion Channels / metabolism*

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Micelles
  • Voltage-Dependent Anion Channels
  • tanespimycin