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

Author(s)

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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS; v. 42, n. 2, p. 213-220, APR 2017.
• Web of Science Citations: 4

Abstract

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)

• FAPESP's process: 11/21700-5 - The use of bacteria from gastrointestinal tract and filamentous fungi for biotransformation studies of naphthoquinones
• Grantee: Niege Araçari Jacometti Cardoso Furtado
• Support type: Regular Research Grants
• FAPESP's process: 11/01303-1 - Biotransformation of ²-lapachone using microbial cultures: an alternative to in vitro metabolism studies
• Grantee: Camila Raquel Paludo
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 09/51812-0 - Development of a platform for the study of in vitro and in vivo metabolism of natural products, a need for pre-clinical testing system
• Grantee: Norberto Peporine Lopes
• Support type: BIOTA-FAPESP Program - Thematic Grants