Inactivation of beta-Lapachone Cytotoxicity by Filamentous Fungi that Mimic the Human Blood Metabolism

Autor(es)

Paludo, Camila Raquel ; da Silva-Junior, Eduardo Afonso ; Silva, Eliane de Oliveira ; Vessecchi, Ricardo ; Lopes, Norberto Peporine ; Pupo, Monica Tallarico ; Emery, Flavio da Silva ; Goncalves, Natalia dos Santos ; dos Santos, Raquel Alves ; Jacometti Cardoso Furtado, Niege Aracari

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS; v. 42, n. 2, p. 213-220, APR 2017.
• Citações Web of Science: 4

Resumo

Background and Objectives beta-Lapachone is a drug candidate in phase II clinical trials for treatment of solid tumors. The therapeutic efficacy of beta-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 beta-lapachone human blood phase I metabolites to evaluate their cytotoxic activities. Methods The biotransformation of beta-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 beta-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 beta-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 beta-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 halfmaximal inhibitory concentration (IC50) values of these blapachone metabolites were 33-to 52-fold greater than IC50 values of beta-lapachone. Conclusions The cytotoxic activity of beta-lapachone in vivo may be reduced due to its swift conversion in blood. (AU)

• Processo FAPESP: 11/21700-5 - Utilização de bactérias do trato gastrointestinal e fungos filamentosos para estudos de biotransformação de naftoquinonas
• Beneficiário: Niege Araçari Jacometti Cardoso Furtado
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/01303-1 - Biotransformação da ²-lapachona utilizando culturas microbianas: uma alternativa para estudos de metabolismo in vitro
• Beneficiário: Camila Raquel Paludo
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 09/51812-0 - Desenvolvimento de uma plataforma para o estudo do metabolismo in vivo e in vitro de produtos naturais, uma necessidade para o sistema de ensaios pré-clínicos
• Beneficiário: Norberto Peporine Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático