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

作者：Huang Xiumei; Dong Ying; Bey Erik A; Kilgore Jessica A; Bair Joseph S; Li Long Shan; Patel Malina; Parkinson Elizabeth I; Wang Yiguang; Williams Noelle S; Gao Jinming; Hergenrother Paul J^*; Boothman David A

来源：Cancer Research, 2012, 72(12): 3038-3047.

DOI：10.1158/0008-5472.CAN-11-3135

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 %26quot;bioactivated%26quot; 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.

• 出版日期2012-6-15