title: β-Lapachone Induces NAD(P)H:Quinone Oxidoreductase-1- and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis.
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
  
  
  
  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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Yougen
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Siyu
authors.initials: S
authors.lastname: Chang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (Y.W., X.W., S.C.,W.L., M.L., X.P.); Central Laboratory, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China (Y.W.); and Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (M.L.) xfpang@bio.ecnu.edu.cn.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015513:Oncogene Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D009285:Naphthoquinones; D015513:Oncogene Proteins; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D046988:Proteasome Endopeptidase Complex