Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone.
Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone.
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DOI：
10.1038/srep17066
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发表时间：
2015-11-25
影响因子：
4.6
通讯作者：
Boothman DA
中科院分区：
文献类型：
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作者：
Chakrabarti G;Silvers MA;Ilcheva M;Liu Y;Moore ZR;Luo X;Gao J;Anderson G;Liu L;Sarode V;Gerber DE;Burma S;DeBerardinis RJ;Gerson SL;Boothman DA
碱基切除修复(BER)是胰腺导管腺癌(PDA)生存的重要途径。由于缺乏肿瘤选择性和非常有限的疗效，靶向该修复途径的尝试失败了。NAD(P)H：Quone Oxidreductase1(NQO1)生物活性药物？拉帕酮(ARQ761)可以提供肿瘤选择性和增强的BER抑制协同作用。？-Lapachone经历NQO1依赖的徒劳氧化还原循环，产生大量的细胞内过氧化氢水平和氧化DNA损伤，刺激聚(ADP-核糖)聚合酶1(PARP1)的过度激活。NAD+/ATP迅速耗尽和程序性坏死。为了确定修复伯拉帕酮诱导的DNA碱基损伤所必需的BER调节剂，一个集中的合成致死RNAi筛选表明，沉默BER支架蛋白XRCC1，敏化PDA细胞。相反，耗尽OGG1N-糖基酶可以使细胞免于因伯拉普诱导的死亡和钝化的PARP1过度激活。与XRCC1基因敲除或甲氧基胺(MeOX)(一种无嘧啶/无嘌呤(AP)修饰剂)联合使用，在PDA、NSCLC、乳腺癌和头颈部癌症中导致NQO1依赖的协同杀伤。OGG1基因敲除、双香豆素治疗或NQO1-癌细胞幸免于难。MeOX+伯拉帕酮暴露可导致DNA双链断裂增加、PARP1过度激活和TUNEL+程序性坏死。联合治疗产生了显著的抗肿瘤活性，增强了肿瘤组织中PARP1的过度激活，并改善了携带MiaPaca2来源的异种移植的小鼠的存活，有33%的明显治愈。意义：仅靶向碱基切除修复(BER)对胰腺癌或其他癌症的治疗潜力有限，因为普遍缺乏肿瘤选择性。在这里，我们提出了一种治疗策略，使BER抑制肿瘤选择性和NQO1依赖于大多数实体肿瘤的治疗，特别是对胰腺癌。
Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.