title: Inactivation of β-Lapachone Cytotoxicity by Filamentous Fungi that Mimic the Human Blood Metabolism.
abstract: OBJECTIVE
  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 IC50values of β-lapachone.
  
  
  CONCLUSIONS
  The cytotoxic activity of β-lapachone in vivo may be reduced due to its swift conversion in blood.
authors.affiliation: 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.
authors.forename: Camila Raquel
authors.initials: CR
authors.lastname: Paludo
authors.affiliation: 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.
authors.forename: Eduardo Afonso
authors.initials: EA
authors.lastname: da Silva-Junior
authors.affiliation: 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.
authors.forename: Eliane
authors.initials: E
authors.lastname: de Oliveira Silva
authors.affiliation: 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.|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.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vessecchi
authors.affiliation: 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.
authors.forename: Norberto
authors.initials: N
authors.lastname: Peporine Lopes
authors.affiliation: 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.
authors.forename: Mônica
authors.initials: M
authors.lastname: Tallarico Pupo
authors.affiliation: 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.
authors.forename: Flavio
authors.initials: F
authors.lastname: da Silva Emery
authors.affiliation: Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Av. Armando de Sales Oliveira, 201, Franca, São Paulo, 14404-600, Brazil.
authors.forename: Natália
authors.initials: N
authors.lastname: Dos Santos Gonçalves
authors.affiliation: Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Av. Armando de Sales Oliveira, 201, Franca, São Paulo, 14404-600, Brazil.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alves Dos Santos
authors.affiliation: 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.
authors.forename: Niege Araçari
authors.initials: NA
authors.lastname: Jacometti Cardoso Furtado
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005658:Fungi / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D009089:Mucor / Q000378:metabolism; D009285:Naphthoquinones / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; C014638:beta-lapachone