Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
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...
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2005
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10780432_v11_n8_p3055_Reinicke http://hdl.handle.net/20.500.12110/paper_10780432_v11_n8_p3055_Reinicke |
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paper:paper_10780432_v11_n8_p3055_Reinicke2023-06-08T16:05:32Z Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels Burton, Gerardo 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 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. 2005 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10780432_v11_n8_p3055_Reinicke http://hdl.handle.net/20.500.12110/paper_10780432_v11_n8_p3055_Reinicke |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Burton, Gerardo Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| topic_facet |
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 |
| description |
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. |
| author |
Burton, Gerardo |
| author_facet |
Burton, Gerardo |
| author_sort |
Burton, Gerardo |
| title |
Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| title_short |
Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| title_full |
Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| title_fullStr |
Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| title_full_unstemmed |
Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels |
| title_sort |
development of β-lapachone prodrugs for therapy against human cancer cells with elevated nad(p)h:quinone oxidoreductase 1 levels |
| publishDate |
2005 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10780432_v11_n8_p3055_Reinicke http://hdl.handle.net/20.500.12110/paper_10780432_v11_n8_p3055_Reinicke |
| work_keys_str_mv |
AT burtongerardo developmentofblapachoneprodrugsfortherapyagainsthumancancercellswithelevatednadphquinoneoxidoreductase1levels |
| _version_ |
1768542376023818240 |