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

编号：

b5ba5984-76ee-43d9-9d4b-5a2fe4af4787
作者：

Wu, Yougen^[1,2,3] Wang, Xue^[1,2] Chang, Siyu^[1,2] Lu, Weiqiang^[1,2] Liu, Mingyao^[1,2,4] Pang, Xiufeng^[1,2]
语种：

English
期刊：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS ISSN：0022-3565 2016 年 357 卷 3 期 (466 - 475) ; JUN
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摘要：

beta-Lapachone [beta-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 beta-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 beta-lap were different from that of the conventional Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. As a consequence of Hsp90 cleavage, Hsp90-associated onco-proteins, 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 beta-lap-mediated Hsp90 cleavage. In addition to its cytotoxicity, beta-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, beta-lap markedly suppressed the growth and angiogenesis of human lung cancer xenografts in nude mice and decreased the levels of receptorinteracting protein, AKT, CDK4, and CD31 in the solid tumors. Unlike other NQO1-dependent cytotoxic quinones, such as streptonigrin, menadione, mitomycin, and 17-allylamino-17demethoxygeldanamycin, beta-lap was the only agent that could cause Hsp90 cleavage. Taken together, our results suggest a crucial mechanism underlying the antitumor efficacy of beta-lap.
推荐引用方式
GB/T 7714：

Wu Yougen,Wang Xue,Chang Siyu, et al. beta-Lapachone Induces NAD(P)H: Quinone Oxidoreductase-1-and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis [J].JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2016,357(3):466-475.
APA：

Wu Yougen,Wang Xue,Chang Siyu,Lu Weiqiang,&Pang Xiufeng.(2016).beta-Lapachone Induces NAD(P)H: Quinone Oxidoreductase-1-and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis .JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,357(3):466-475.
MLA：

Wu Yougen, et al. "beta-Lapachone Induces NAD(P)H: Quinone Oxidoreductase-1-and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis" .JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 357,3(2016):466-475.

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