An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis

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

Research output: Contribution to journalArticle

Abstract

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. 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 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.

Original languageEnglish (US)
Pages (from-to)3038-3047
Number of pages10
JournalCancer Research
Volume72
Issue number12
DOIs
StatePublished - Jun 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Huang, X., Dong, Y., Bey, E. A., Kilgore, J. A., Bair, J. S., Li, L. S., Patel, M., Parkinson, E. I., Wang, Y., Williams, N. S., Gao, J., Hergenrother, P. J., & Boothman, D. A. (2012). An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis. Cancer Research, 72(12), 3038-3047. https://doi.org/10.1158/0008-5472.CAN-11-3135