Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent
Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent
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DOI：
10.1016/j.taap.2014.10.012
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发表时间：
2014-12-15
影响因子：
3.8
通讯作者：
Jia, Zhenquan
中科院分区：
文献类型：
--
作者：
Li, Jason Z.;Ke, Yuebin;Jia, Zhenquan
源自拉帕乔树的β-拉帕酮（β-Lp）是一种潜在的新型抗癌剂，目前正在进行临床试验。先前的研究表明，NAD(P)H:醌氧化还原酶 1 (NQO1) 催化的 β-Lp 氧化还原激活是其杀死癌细胞的原因。然而，这种效应的确切机制仍然很大程度上未知。该研究利用化学发光和电子顺磁共振（EPR）自旋捕获技术，首次证明了黑色素瘤B16-F10和肝细胞癌HepG2癌细胞中线粒体和NQO1介导的β-拉帕酮氧化还原激活过程中ROS的实时形成。 ES936（一种高选择性 NQO1 抑制剂）和鱼藤酮（一种线粒体电子传递链 (METC) 复合物 I 的选择性抑制剂）被发现可显着阻断 B16-F10 细胞中 β-Lp 介导的氧化还原激活。在 HepG2 细胞中，ES936 抑制 β-Lp 介导的氧自由基形成约 80%，而鱼藤酮没有产生显着效果。这些结果揭示了 METC 和 NQO1 对 β-拉帕酮诱导的 ROS 形成和癌细胞杀伤的不同贡献。在不表达高 NQO1 活性的黑色素瘤 B16-F10 细胞中，NOQ1 和 METC 在 β-Lp 氧化还原激活中发挥着关键作用。相反，在表达极高 NQO1 活性的肝细胞癌 HepG2 细胞中，β-Lp 的氧化还原激活主要由 NQO1 介导（METC 发挥次要作用）。这些发现将有助于我们了解β-拉帕酮如何选择性杀死癌细胞，并提高我们制定策略的能力，以增强这种潜在新药的抗癌功效，同时最大限度地减少其对正常细胞可能产生的不利影响。 (C) 2014 Elsevier Inc. 保留所有权利。
Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16-F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by similar to 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16-F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. (C) 2014 Elsevier Inc. All rights reserved.