β-Lapachone Induces NAD(P)H:Quinone Oxidoreductase-1- and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis

J Pharmacol Exp Ther. 2016 Jun;357(3):466-75. doi: 10.1124/jpet.116.232694. Epub 2016 Apr 5.

Abstract

β-Lapachone [β-lap; 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione] is a novel anticancer drug currently under investigation in phase I/II clinical trials. However, the mechanism underlying its clinical efficacy remains unclear. In this study, we found that β-lap provoked the cleavage of heat shock protein 90 (Hsp90) in

Nad(p)h: quinone oxidoreductase-1 (NQO1)-expressing lung and prostate cancer cells as well as in primary human umbilical vein endothelial cells (HUVECs). These actions of β-lap were different from that of the conventional Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. As a consequence of Hsp90 cleavage, Hsp90-associated oncoproteins, such as receptor-interacting protein, Raf-1, AKT, and CDK4, were degraded in treated cancer cells, and key receptor tyrosine kinases such as vascular endothelial cell growth factor receptor-2 and Her-2 were degraded in treated HUVECs through a proteasomal system. Further results revealed that specific inhibitors of NQO1 and reactive oxygen species could dramatically reduce β-lap-mediated Hsp90 cleavage. In addition to its cytotoxicity, β-lap effectively inhibited angiogenesis by suppressing tube formation and the invasion of HUVECs in vitro, rat aortic microvascular sprouts ex vivo, and mouse corneal neovascularization in vivo. Furthermore, β-lap markedly suppressed the growth and angiogenesis of human lung cancer xenografts in nude mice and decreased the levels of receptor-interacting protein, AKT, CDK4, and CD31 in the solid tumors. Unlike other NQO1-dependent cytotoxic quinones, such as streptonigrin, menadione, mitomycin, and 17-allylamino-17-demethoxygeldanamycin, β-lap was the only agent that could cause Hsp90 cleavage. Taken together, our results suggest a crucial mechanism underlying the antitumor efficacy of β-lap.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aorta / drug effects
  • Aorta / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*
  • Naphthoquinones / pharmacology*
  • Naphthoquinones / therapeutic use
  • Neovascularization, Pathologic / drug therapy
  • Oncogene Proteins / metabolism
  • Oxidative Stress / drug effects*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability / drug effects
  • Proteolysis / drug effects*
  • Rats
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Naphthoquinones
  • Oncogene Proteins
  • beta-lapachone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Proteasome Endopeptidase Complex