Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels

• Autores: Reinicke, K.E.; Bey, E.A.; Bentle, M.S.; Pink, J.J.; Ingalls, S.T.; Hoppel, C.L.; Misico, R.I.; Arzac, G.M.; Burton, G.; Bornmann, W.G.; Sutton, D.; Gao, J.; Boothman, D.A.
• Año de publicación: 2005
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Clin. Cancer Res. 2005;11(8):3055-3064
• Materia: 2,2 dimethyl 6 (4 bromophenylimino) 3,4,5,6 tetrahydro 2h naphth[1,2 b]oxin 5 one; 2,2 dimethyl 6 (4 methoxyphenylimino) 3,4,5,6 tetrahydro 2h naphth[1,2 b]oxin 5 one; 2,2 dimethyl 6 (4 methylphenylimino) 3,4,5,6 tetrahydro 2h naphth[1,2 b]oxin 5 one; 2,2 dimethyl 6 (4 nitrophenylimino) 3,4,5,6 tetrahydro 2h naphth[1,2 b]oxin 5 one; 2,2 dimethyl 6 phenylimino 3,4,5,6 tetrahydro 2h naphth[1,2 b]oxin 5 one; 4 bromophenylimine lapachone; 4 methoxyphenylimine lapachone; 4 methylphenylimine lapachone; 4 nitrophenylimine lapachone; acetylcysteine; acid; beta lapachone derivative; calpain; diluent; mu calpain; phenylimine lapachone; prodrug; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone); reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone) 1; unclassified drug; water; acidity; antineoplastic activity; article; cancer tissue; cell death; cell killing; chemical modification; controlled study; cytotoxicity; dilution; drug hydrolysis; drug selectivity; electron; electrospray mass spectrometry; enzyme activation; enzyme assay; high performance liquid chromatography; human; human cell; nuclear magnetic resonance; pH; priority journal; toxicity; ultraviolet spectrophotometry; Cell Division; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Magnetic Resonance Spectroscopy; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Prodrugs; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Structure-Activity Relationship
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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. © 2005 American Association for Cancer Research.
Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.