Artículo

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. "Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels" (2005) Clinical Cancer Research. 11(8):3055-3064
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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. © 2005 American Association for Cancer Research.

Registro:

Documento: Artículo
Título:Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
Autor: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.
Filiación:Lab. of Molecular Stress Responses, Case Western Reserve University, Cleveland, OH, United States
Department of Biochemistry, Case Western Reserve University, Cleveland, OH, United States
Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, United States
Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States
Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
Medical Research Service, Louis Stokes Vet. Aff. Med. Center, Cleveland, OH, United States
Depto. de Quím. Orgán., Fac. de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Department of Molecular Imaging, M.D. Anderson University, Houston, TX, United States
Lab. of Molecular Stress Responses, Dept. Radiat. Oncol. and Pharmacol., Case Comprehensive Cancer Center, 2103 Cornell Avenue, WRB-3531 West, Cleveland, OH 44106-7285, United States
Palabras clave: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
Año:2005
Volumen:11
Número:8
Página de inicio:3055
Página de fin:3064
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-04-2185
Título revista:Clinical Cancer Research
Título revista abreviado:Clin. Cancer Res.
ISSN:10780432
CODEN:CCREF
CAS:acetylcysteine, 616-91-1; calpain, 78990-62-2; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone), 9032-20-6; water, 7732-18-5; beta-lapachone, 4707-32-8; NAD(P)H Dehydrogenase (Quinone), EC 1.6.99.2; Naphthoquinones; NQO1 protein, human, EC 1.6.99.2; Prodrugs
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Citas:

---------- APA ----------
Reinicke, K.E., Bey, E.A., Bentle, M.S., Pink, J.J., Ingalls, S.T., Hoppel, C.L., Misico, R.I.,..., Boothman, D.A. (2005) . Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clinical Cancer Research, 11(8), 3055-3064.
http://dx.doi.org/10.1158/1078-0432.CCR-04-2185
---------- CHICAGO ----------
Reinicke, K.E., Bey, E.A., Bentle, M.S., Pink, J.J., Ingalls, S.T., Hoppel, C.L., et al. "Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels" . Clinical Cancer Research 11, no. 8 (2005) : 3055-3064.
http://dx.doi.org/10.1158/1078-0432.CCR-04-2185
---------- MLA ----------
Reinicke, K.E., Bey, E.A., Bentle, M.S., Pink, J.J., Ingalls, S.T., Hoppel, C.L., et al. "Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels" . Clinical Cancer Research, vol. 11, no. 8, 2005, pp. 3055-3064.
http://dx.doi.org/10.1158/1078-0432.CCR-04-2185
---------- VANCOUVER ----------
Reinicke, K.E., Bey, E.A., Bentle, M.S., Pink, J.J., Ingalls, S.T., Hoppel, C.L., et al. Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Clin. Cancer Res. 2005;11(8):3055-3064.
http://dx.doi.org/10.1158/1078-0432.CCR-04-2185