title: 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.
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bey
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kilgore
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bair
authors.forename: Long-Shan
authors.initials: LS
authors.lastname: Li
authors.forename: Malina
authors.initials: M
authors.lastname: Patel
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Parkinson
authors.forename: Yiguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D011809:Quinones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C550580:deoxynyboquinone; D009243:NAD; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C014638:beta-lapachone; D000255:Adenosine Triphosphate; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium