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.
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Authors | 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 |
Journal | Cancer research
(Cancer Res)
Vol. 72
Issue 12
Pg. 3038-47
(Jun 15 2012)
ISSN: 1538-7445 [Electronic] United States |
PMID | 22532167
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
- Egtazic Acid
- beta-lapachone
- Adenosine Triphosphate
- NAD(P)H Dehydrogenase (Quinone)
- NQO1 protein, human
- PARP1 protein, human
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
- Calcium
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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) Polymerase-1
- Poly(ADP-ribose) Polymerases
(genetics, metabolism)
- Quinones
(pharmacology)
- RNA Interference
- RNA, Small Interfering
- Reactive Oxygen Species
(metabolism)
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