Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.
Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.
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DOI：
10.1016/j.ccell.2016.11.006
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发表时间：
2016-12-12
期刊：
影响因子：
50.3
通讯作者：
Boothman DA
中科院分区：
文献类型：
--
作者：
Huang X;Motea EA;Moore ZR;Yao J;Dong Y;Chakrabarti G;Kilgore JA;Silvers MA;Patidar PL;Cholka A;Fattah F;Cha Y;Anderson GG;Kusko R;Peyton M;Yan J;Xie XJ;Sarode V;Williams NS;Minna JD;Beg M;Gerber DE;Bey EA;Boothman DA
阻断DNA修复的治疗药物，包括聚（ADP-核糖）聚合酶（PARP）抑制剂，由于缺乏肿瘤选择性而失败。当PARP抑制剂和β-拉帕酮组合时，协同抗肿瘤活性来自持续的NAD（P）H水平，其重新激发NQO 1依赖性无效氧化还原药物再循环。显著的耗氧速率/活性氧物质导致DNA损伤急剧增加，由于PARP抑制而无法修复。在NQO 1+癌症（如非小细胞肺癌、胰腺癌和乳腺癌）中，细胞死亡机制从PARP 1过度活化介导的程序性坏死（β-拉帕醌单药治疗）转变为PARP抑制剂和β-拉帕醌协同肿瘤选择性、半胱天冬酶依赖性细胞凋亡。在人原位胰腺和非小细胞肺异种移植模型中观察到协同抗肿瘤疗效和生存期延长，扩大了PARP抑制剂在人癌症治疗中的使用和疗效。
Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen consumption rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small cell lung, pancreatic and breast, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
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DOI：
10.1016/j.jconrel.2014.12.027
发表时间：
2015-02-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Ma X;Huang X;Moore Z;Huang G;Kilgore JA;Wang Y;Hammer S;Williams NS;Boothman DA;Gao J
通讯作者：
Gao J
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。
影响因子：
5.7
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
通讯作者：
Boothman DA
影响因子：
3.7
作者：
Planchon, SM;Pink, JJ;Boothman, DA
通讯作者：
Boothman, DA
影响因子：
28.2
作者：
Skoulidis F;Byers LA;Diao L;Papadimitrakopoulou VA;Tong P;Izzo J;Behrens C;Kadara H;Parra ER;Canales JR;Zhang J;Giri U;Gudikote J;Cortez MA;Yang C;Fan Y;Peyton M;Girard L;Coombes KR;Toniatti C;Heffernan TP;Choi M;Frampton GM;Miller V;Weinstein JN;Herbst RS;Wong KK;Zhang J;Sharma P;Mills GB;Hong WK;Minna JD;Allison JP;Futreal A;Wang J;Wistuba II;Heymach JV
通讯作者：
Heymach JV
影响因子：
8.8
作者：
Murray, J.;Thomas, H.;Berry, P.;Kyle, S.;Patterson, M.;Jones, C.;Los, G.;Hostomsky, Z.;Plummer, E. R.;Boddy, A. V.;Curtin, N. J.
通讯作者：
Curtin, N. J.