American Association for Cancer Research
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Supplementary Figures 4-5 from An NQO1 Substrate with Potent Antitumor Activity That Selectively Kills by PARP1-Induced Programmed Necrosis

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journal contribution
posted on 2023-03-30, 21:02 authored by Xiumei Huang, Ying Dong, Erik A. Bey, Jessica A. Kilgore, Joseph S. Bair, Long-Shan Li, Malina Patel, Elizabeth I. Parkinson, Yiguang Wang, Noelle S. Williams, Jinming Gao, Paul J. Hergenrother, David A. Boothman

PDF file - 514K, NQO1-dependent nucleotide depletion in response to DNQ. Supplemental Figure 5. PARP1 hyperactivation is essential for NQO1-dependent ATP loss.



Agents, such as β-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 β-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. Short-term 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 β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-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.