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

Agents, such as b-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 spectrumof cancer cells in anNQO1dependent manner with greater potency than b-lapachone. Deoxynyboquinone lethality relies on NQO1dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NADþ/ATP depletion that stimulate Ca2þ–dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Shortterm exposure of NQO1þ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1 cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1þ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2þ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with b-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to b-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. 2012 AACR.