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

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. 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.
AuthorsXiumei 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
JournalCancer research (Cancer Res) Vol. 72 Issue 12 Pg. 3038-47 (Jun 15 2012) ISSN: 1538-7445 [Electronic] United States
PMID22532167 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Naphthoquinones
  • Quinones
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • deoxynyboquinone
  • NAD
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • beta-lapachone
  • Egtazic Acid
  • Adenosine Triphosphate
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • PARP1 protein, human
  • Poly(ADP-ribose) Polymerases
  • Calcium
Topics
  • Adenosine Triphosphate (metabolism)
  • Antineoplastic Agents (pharmacology)
  • Calcium (metabolism)
  • Cell Line, Tumor
  • DNA Damage (drug effects)
  • Egtazic Acid (analogs & derivatives, pharmacology)
  • Humans
  • NAD (metabolism)
  • NAD(P)H Dehydrogenase (Quinone) (genetics, metabolism)
  • Naphthoquinones (pharmacology)
  • Necrosis
  • Neoplasms (drug therapy, metabolism, pathology)
  • Oxidation-Reduction (drug effects)
  • Poly(ADP-ribose) Polymerases (genetics, metabolism)
  • Quinones (pharmacology)
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species (metabolism)

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