Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

Huang Xiumei; Motea Edward A.; Moore Zachary R.; Yao Jun; Dong Ying; Chakrabarti Gaurab; Kilgore Jessica A.; Silvers Molly A.; Patidar Praveen L.; Cholka Agnieszka; Fattah Farjana; Cha Yoonjeong; Anderson Glenda G.; Kusko Rebecca; Peyton Michael; Yan Jingsheng; Xie Xian-Jin; Sarode Venetia; Williams Noelle S.; Minna John D.; Beg Muhammad; Gerber David E.; Bey Erik A.; Boothman David A.

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Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

机译：利用NQO1生物活化药物用于肿瘤选择性使用聚（ADP-核糖）聚合酶抑制剂

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Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and beta-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 cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with beta-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and beta-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.

机译：阻止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效。当组合PARP抑制剂和β-乙酰酮时，来自持续NAD（P）H级别的协同抗肿瘤活性会使加油NQO1依赖杂交氧化还原药物再循环的持续NAD（P）H级别。显着的氧气消耗速率/反应性氧物质导致由于PARP抑制而不会修复的剧烈DNA病变。在NQO1（+）癌症中，如非小细胞肺，胰腺和乳腺癌，细胞死亡机制从PARP1多动激活介导的编程坏死与β-乙酰醌单疗法进行协同肿瘤选择性，依赖于PARP的Caspase依赖性细胞凋亡抑制剂和β-乙酰酮。在人原位胰腺和非小细胞肺异种移植模型中注意到协同抗肿瘤功效和延长的存活，扩张使用和PARP抑制剂对人体癌症治疗的疗效。

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《Cancer Cell》 |2016年第6期|共13页
作者
Huang Xiumei; Motea Edward A.; Moore Zachary R.; Yao Jun; Dong Ying; Chakrabarti Gaurab; Kilgore Jessica A.; Silvers Molly A.; Patidar Praveen L.; Cholka Agnieszka; Fattah Farjana; Cha Yoonjeong; Anderson Glenda G.; Kusko Rebecca; Peyton Michael; Yan Jingsheng; Xie Xian-Jin; Sarode Venetia; Williams Noelle S.; Minna John D.; Beg Muhammad; Gerber David E.; Bey Erik A.; Boothman David A.;
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UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UTSW SCCC Dept Biochem Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

Immuneering Corp One Broadway 14th Floor Cambridge MA 02142 USA;

5Degrees Bio Inc 111 North Market St 300 San Jose CA 95113 USA;

Immuneering Corp One Broadway 14th Floor Cambridge MA 02142 USA;

UTSW Dept Internal Med Div Hematol Oncol Dallas TX 75390 USA;

UTSW Dept Biostat Dallas TX 75390 USA;

UTSW Dept Biostat Dallas TX 75390 USA;

UTSW Dept Pathol Dallas TX 75390 USA;

UTSW SCCC Dept Biochem Dallas TX 75390 USA;

UTSW Dept Internal Med Div Hematol Oncol Dallas TX 75390 USA;

UTSW Dept Internal Med Div Hematol Oncol Dallas TX 75390 USA;

UTSW Dept Internal Med Div Hematol Oncol Dallas TX 75390 USA;

West Virginia Univ Dept Pharmaceut Sci Inst Canc Morgantown WV 26506 USA;

UT Southwestern Med Ctr UTSW SCCC Dept Pharmacol Dallas TX 75390 USA;

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正文语种 eng
中图分类肿瘤学;
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专利

1. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors [J] . Huang Xiumei, Motea Edward A., Moore Zachary R., Cancer Cell . 2016,第6期

机译：利用NQO1生物活化药物用于肿瘤选择性使用聚（ADP-核糖）聚合酶抑制剂
2. Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone [J] . Gaurab Chakrabarti, Molly A. Silvers, Mariya Ilcheva, Scientific reports. . 2015,第1期

机译：使用NQO1生物可活化药物β-拉帕酮在胰腺癌中选择性使用DNA碱基切除修复抑制
3. Tumor-selective, futile redox cycle-induced bystander effects elicited by NQO1 bioactivatable radiosensitizing drugs in triple-negative breast cancers [J] . CaoL., LiL.S., SpruellC., Antioxidants and redox signalling . 2014,第2期

机译：NQO1可生物激活的放射增敏药物在三阴性乳腺癌中引起的肿瘤选择性，无效的氧化还原循环诱导的旁观者效应
4. DESIGN AND SYNTHESIS OF NOVEL POLY ADP-RIBOSE POLYMERASE 1(PARP1)INHIBITORS FOR THE TREATMENT OF SOLID TUMORS [C] . J.Priyancy, D.P.Bhumika Conference on Drug Design and Discovery Technologies . 2020

机译：用于治疗实体肿瘤的新型聚ADP-核糖聚合酶1（PARP1）抑制剂的设计与合成
5. Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity [D] . Velagapudi, Uday Kiran. 2019

机译：聚（ADP-核糖）聚合酶抑制剂的设计与合成：腺苷袋结合基序附录对3-氧代-2,3-二氢苯并呋喃-7-甲酰胺对效力和选择性的影响
6. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase (PARP) Inhibitors [O] . Xiumei Huang, Edward A. Motea, Zachary R. Moore, -1

机译：利用NQO1可生物激活药物用于聚（ADP-核糖）聚合酶（PARP）抑制剂的肿瘤选择性使用
7. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors [O] . Xiumei Huang, Edward A. Motea, Zachary R. Moore, 2016

机译：利用NQO1生物活化药物用于肿瘤选择性使用聚（ADP-核糖）聚合酶抑制剂

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

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