An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.
Cancer Res
; 72(12): 3038-47, 2012 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-22532167
ABSTRACT
Agents, such as ß-lapachone, that target the redox enzyme, NAD(P)Hquinone 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 ß-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 ß-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinonas
/
NAD(P)H Desidrogenase (Quinona)
/
Poli(ADP-Ribose) Polimerases
/
Neoplasias
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article