Camila Raquel Paludo1, Eduardo Afonso da Silva-Junior1, Eliane de Oliveira Silva1, Ricardo Vessecchi2,3, Norberto Peporine Lopes3, Mônica Tallarico Pupo1, Flavio da Silva Emery1, Natália Dos Santos Gonçalves4, Raquel Alves Dos Santos4, Niege Araçari Jacometti Cardoso Furtado5. 1. Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil. 2. Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14040-901, Brazil. 3. Núcleo de Pesquisa em Produtos Naturais e Sintéticos, Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil. 4. Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Av. Armando de Sales Oliveira, 201, Franca, São Paulo, 14404-600, Brazil. 5. Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, São Paulo, 14040-903, Brazil. niege@fcfrp.usp.br.
Abstract
BACKGROUND AND OBJECTIVES: β-Lapachone is a drug candidate in phase II clinical trials for treatment of solid tumors. The therapeutic efficacy of β-lapachone is closely related to its metabolism, since this o-naphthoquinone produces cytotoxic effect after intracellular bioreduction by reactive oxygen species formation. The aim of this study was to produce β-lapachone human blood phase I metabolites to evaluate their cytotoxic activities. METHODS: The biotransformation of β-lapachone was performed using Mucor rouxii NRRL 1894 and Papulaspora immersa SS13. The metabolites were isolated and their chemical structures determined from spectrometric and spectroscopic data. Cell cytotoxicity assays were carried out with β-lapachone and its metabolites using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. RESULTS: Microbial transformation of β-lapachone by filamentous fungi resulted in the production of five metabolites identical to those found during human blood metabolism, a novel metabolite and a product stated before only in a synthetic procedure. The analysis of the results showed that β-lapachone metabolites were not cytotoxic for the neoplastic cell line SKBR-3 derived from human breast cancer and the normal human fibroblast cell line GM07492-A. The cytotoxic activity assay against the neoplastic cell line SKBR-3 revealed that the lowest half-maximal inhibitory concentration (IC50) values of these β-lapachone metabolites were 33- to 52-fold greater than IC50 values of β-lapachone. CONCLUSIONS: The cytotoxic activity of β-lapachone in vivo may be reduced due to its swift conversion in blood.
BACKGROUND AND OBJECTIVES: β-Lapachone is a drug candidate in phase II clinical trials for treatment of solid tumors. The therapeutic efficacy of β-lapachone is closely related to its metabolism, since this o-naphthoquinone produces cytotoxic effect after intracellular bioreduction by reactive oxygen species formation. The aim of this study was to produce β-lapachone human blood phase I metabolites to evaluate their cytotoxic activities. METHODS: The biotransformation of β-lapachone was performed using Mucor rouxii NRRL 1894 and Papulaspora immersa SS13. The metabolites were isolated and their chemical structures determined from spectrometric and spectroscopic data. Cell cytotoxicity assays were carried out with β-lapachone and its metabolites using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. RESULTS: Microbial transformation of β-lapachone by filamentous fungi resulted in the production of five metabolites identical to those found during human blood metabolism, a novel metabolite and a product stated before only in a synthetic procedure. The analysis of the results showed that β-lapachone metabolites were not cytotoxic for the neoplastic cell line SKBR-3 derived from human breast cancer and the normal human fibroblast cell line GM07492-A. The cytotoxic activity assay against the neoplastic cell line SKBR-3 revealed that the lowest half-maximal inhibitory concentration (IC50) values of these β-lapachone metabolites were 33- to 52-fold greater than IC50 values of β-lapachone. CONCLUSIONS: The cytotoxic activity of β-lapachone in vivo may be reduced due to its swift conversion in blood.
Authors: Clarissa S Capel; Ana C D de Souza; Tatiane C de Carvalho; João P B de Sousa; Sérgio R Ambrósio; Carlos H G Martins; Wilson R Cunha; Rosario H Galán; Niege A J C Furtado Journal: J Ind Microbiol Biotechnol Date: 2011-01-13 Impact factor: 3.346
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Authors: Xiu-Sheng Miao; Pengfei Song; Ronald E Savage; Caiyun Zhong; Rui-Yang Yang; Darin Kizer; Hui Wu; Erika Volckova; Mark A Ashwell; Jeffrey G Supko; Xiaoying He; Thomas C K Chan Journal: Drug Metab Dispos Date: 2008-01-07 Impact factor: 3.579
Authors: Rui-Yang Yang; Darin Kizer; Hui Wu; Erika Volckova; Xiu-Sheng Miao; Syed M Ali; Manish Tandon; Ronald E Savage; Thomas C K Chan; Mark A Ashwell Journal: Bioorg Med Chem Date: 2008-04-01 Impact factor: 3.461