An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.
An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.
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DOI：
10.1158/0008-5472.can-11-3135
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发表时间：
2012-06-15
期刊：
影响因子：
11.2
通讯作者：
Boothman DA
中科院分区：
文献类型：
--
作者：
Huang X;Dong Y;Bey EA;Kilgore JA;Bair JS;Li LS;Patel M;Parkinson EI;Wang Y;Williams NS;Gao J;Hergenrother PJ;Boothman DA
靶向氧化还原酶NAD（P）H：醌氧化还原酶1（NQO 1）以诱导实体瘤中的程序性坏死的药剂（如β-拉帕酮）已显示出巨大的前景，但需要更有效的肿瘤选择性化合物。在这里，我们报告说，deoxynyboquinone杀死广泛的癌细胞在NQO 1依赖的方式与更大的效力比β-拉帕醌。脱氧苯醌的致死性依赖于NQO 1依赖的无用的氧化还原循环，其消耗氧气并产生大量的活性氧（ROS）。升高的ROS水平引起广泛的DNA损伤、PARP 1过度活化和严重的NAD+/ATP耗竭，其刺激Ca 2+依赖性程序性坏死，这是这类新型NQO 1“生物活化”药物所特有的。NQO 1+细胞短期暴露于脱氧尼波醌足以引发细胞死亡，尽管基因匹配的NQO 1 −细胞不受影响。此外，siRNA介导的NQO 1或PARP 1敲除使NQO 1+细胞免于短期致死。用BAPTA-AM（一种胞质Ca 2+螯合剂）或过氧化氢酶（酶促H2 O2清除剂）预处理细胞足以挽救脱氧尼泊醌诱导的致死性，如β-拉帕醌所示。体内研究显示脱氧尼波醌与β-拉帕醌具有相同的抗肿瘤功效，但效力高6倍。PARP 1过度活化和ATP的急剧丢失在肿瘤中被发现，但在相关的正常肺组织中没有。我们的研究结果为脱氧尼波醌作为一种有效的化疗药物治疗广泛的具有治疗挑战性的实体瘤（如胰腺癌和肺癌）提供了临床前概念验证。
Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+/ATP depletion that stimulate Ca2+–dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1− cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers.