An NQO1 Substrate with Potent Antitumor Activity That Selectively Kills by PARP1-Induced Programmed Necrosis

被引:123
作者
Huang, Xiumei [2 ,3 ]
Dong, Ying [2 ,3 ]
Bey, Erik A. [2 ,3 ]
Kilgore, Jessica A. [4 ]
Bair, Joseph S. [1 ]
Li, Long-Shan [2 ,3 ]
Patel, Malina [2 ,3 ]
Parkinson, Elizabeth I. [1 ]
Wang, Yiguang [2 ]
Williams, Noelle S. [4 ]
Gao, Jinming [2 ]
Hergenrother, Paul J. [1 ]
Boothman, David A. [2 ,3 ]
机构
[1] Univ Illinois, Dept Chem, Roger Adams Lab, Urbana, IL 61801 USA
[2] UT SW Med Ctr, Simmons Canc Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[3] UT SW Med Ctr, Simmons Canc Ctr, Dept Radiat Oncol, Dallas, TX 75390 USA
[4] UT SW Med Ctr, Simmons Canc Ctr, Dept Biochem, Dallas, TX 75390 USA
关键词
BETA-LAPACHONE; NAD(P)H-QUINONE OXIDOREDUCTASE; CANCER-CELLS; DT-DIAPHORASE; PANCREATIC-CANCER; HUMAN LUNG; THERAPY; APOPTOSIS; TUMORS; DEATH;
D O I
10.1158/0008-5472.CAN-11-3135
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Agents, such as beta-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 beta-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. Shortterm 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 beta-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to beta-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. Cancer Res; 72(12); 3038-47. (C)2012 AACR.
引用
收藏
页码:3038 / 3047
页数:10
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