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

Abstract

b-Lapachone [b-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 b-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 b-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 b-lap-mediated Hsp90 cleavage. In addition to its cytotoxicity, b-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, b-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-17-demethoxygeldanamycin, b-lap was the only agent that could cause Hsp90 cleavage. Taken together, our results suggest a crucial mechanism underlying the antitumor efficacy of b-lap.

Nutritional Stress in Head and Neck Cancer Originating Cell Lines: The Sensitivity of the NRF2-NQO1 Axis

“…As human fibroblasts WI-38 express NQO1 but are not able to develop the NQO1-mediated redox cycle that could lead to HSP90 (Heat Shock Protein) inhibition upon β-Lapachone induction [44], it was presumed that these cells may have a genotype NQO1*1/*2. When we worked with WI-38 [45], the DNA was preserved from an early passage and kept frozen at −20 °C.…”

Augmentation of cellular NAD+ by NQO1 enzymatic action improves age‐related hearing impairment

“…PARP1 hyperactivation by DNA damage is considered to result in depletion of cellular NAD + and ATP levels (Bai et al, ). Many studies have revealed that the beneficial properties of β‐lap on multiple metabolic syndromes and cisplatin‐mediated ototoxicity/nephrotoxicity were mediated by increased intracellular NAD + levels and SIRT1 activation by inhibiting PARP hyperactivation (Kim, Oh, Shen, et al, ; Wu et al, ). Because PARP1 and SIRTs compete with the same cellular NAD + pool, PARP1 activation has a significant effect on SIRTs activity by decreasing NAD + bioavailability (Bai et al, ).…”

β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers

“…Wu et al . also reported that β-lap effectively inhibited angiogenesis by suppressing tube formation and the invasion of HUVECs in vitro , and suppressed the growth and angiogenesis of human lung cancer xenografts in nude mice 18 . Additionally, numerous lines suggested that the mechanism for which β-lap had become a promising candidate for cancer therapy was dependent on the enzymatic activity of the two-electron oxidoreductase, NQO1 19, 20 .…”