dc.creator | Reinicke, Kathryn E. | |
dc.creator | Bey, Erik A. | |
dc.creator | Bentle, Melissa S. | |
dc.creator | Pink, John J. | |
dc.creator | Ingalls, Stephen T. | |
dc.creator | Hoppel, Charles L. | |
dc.creator | Misico, Rosana Isabel | |
dc.creator | Arzac, Gisella M. | |
dc.creator | Burton, Gerardo | |
dc.creator | Bornmann, William G. | |
dc.creator | Sutton, Damon | |
dc.creator | Gao, Jinming | |
dc.creator | Boothman, David A. | |
dc.date.accessioned | 2019-11-07T17:34:07Z | |
dc.date.accessioned | 2022-10-15T10:06:35Z | |
dc.date.available | 2019-11-07T17:34:07Z | |
dc.date.available | 2022-10-15T10:06:35Z | |
dc.date.created | 2019-11-07T17:34:07Z | |
dc.date.issued | 2005-04 | |
dc.identifier | Reinicke, Kathryn E.; Bey, Erik A.; Bentle, Melissa S.; Pink, John J.; Ingalls, Stephen T.; et al.; Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels; American Association for Cancer Research; Clinical Cancer Research; 11; 8; 4-2005; 3055-3064 | |
dc.identifier | 1078-0432 | |
dc.identifier | http://hdl.handle.net/11336/88169 | |
dc.identifier | CONICET Digital | |
dc.identifier | CONICET | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/4373759 | |
dc.description.abstract | β-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD (P) H:quinone oxidoreductase 1 (NQO1). NQO1 reduces β-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta;-lapachone. Thus, β-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non - small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of β-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to β-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to β-lapachone. Once converted, β-lapachone derivatives caused NQO1-dependent, μ-calpain-mediated cell death in human cancer cells identical to that caused by β-lapachone. Interestingly, coadministration of N-acetyt-L-cysteine prevented derivative-induced cytotoxicity but did not affect β-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of β-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-L-cysteine, preventing their conversion to β-lapachone. The use of β-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation. | |
dc.language | eng | |
dc.publisher | American Association for Cancer Research | |
dc.relation | info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/11/8/3055 | |
dc.relation | info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1158/1078-0432.CCR-04-2185 | |
dc.rights | https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ | |
dc.rights | info:eu-repo/semantics/restrictedAccess | |
dc.subject | B-LAPACHONE DERIVATIVES | |
dc.subject | APOPTOSIS | |
dc.subject | BREAST CANCER | |
dc.subject | NQO1 (DT-diaphorase) | |
dc.title | Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels | |
dc.type | info:eu-repo/semantics/article | |
dc.type | info:ar-repo/semantics/artículo | |
dc.type | info:eu-repo/semantics/publishedVersion | |