Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers.
Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers.
复制标题
过氧化氢酶消除了NQO1阳性乳腺癌中的β-拉帕酮诱导的PARP1过度激活导向的坏死。
DOI：
10.1158/1535-7163.mct-12-0962
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发表时间：
2013-10
影响因子：
5.7
通讯作者：
Boothman DA
中科院分区：
文献类型：
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作者：
Bey EA;Reinicke KE;Srougi MC;Varnes M;Anderson VE;Pink JJ;Li LS;Patel M;Cao L;Moore Z;Rommel A;Boatman M;Lewis C;Euhus DM;Bornmann WG;Buchsbaum DJ;Spitz DR;Gao J;Boothman DA
通过个性化治疗改善患者的结果涉及对代理人的作用机制的彻底了解。β-Lapachone(临床形式，Arq501/Arq761)已被开发用于利用癌症特异性II期解毒酶NAD(P)H：苯醌氧化还原酶(NQO1)的显著升高。NQO1在实体癌中显著升高，包括原发癌和转移性乳腺癌(例如，三阴性(ER-、PR-、Her2/Neu-))乳腺癌。为了通过了解β-拉帕酮的作用机制来确定影响其疗效的细胞因素，我们证实了NQO_1是致死所必需的，并介导了一个无用的氧化还原循环，即每摩尔β-拉帕酮在5分钟内形成约120摩尔的超氧化物。β-Lapachone可诱导乳腺癌细胞产生活性氧(ROS)，刺激依赖于单链断裂的PARP1DNA过度激活，导致必需核苷酸(NAD+/ATPase)的急剧丢失，并引发程序性坏死。虽然PARP1超活性和NQO1表达是β-雷帕酮诱导的致死性的主要决定因素，但过氧化氢酶表达的变化，包括外源性酶处理，引起了显著的细胞保护。因此，过氧化氢酶是一个重要的抗性因子，并突出了过氧化氢作为细胞死亡的专有ROS。外源超氧化物歧化酶增强过氧化氢酶诱导的细胞保护作用。β-拉帕酮诱导的细胞死亡包括AIF从线粒体到细胞核的移位、TUNEL+染色、不典型的PARP1裂解和GAPDHS-亚硝化，这些都被过氧化氢酶消除。我们预测，乳腺癌与相关正常组织中NQO1：过氧化氢酶活性的比率可能是影响β-Lapachone和其他NQO1生物活性药物治疗窗口的主要决定因素。
Improving patient outcome by personalized therapy involves a thorough understanding of an agent’s mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs.