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

• Published in: European journal of drug metabolism and pharmacokinetics 2017-04, Vol.42 (2), p.213-220
• Main Authors: Paludo, Camila Raquel, da Silva-Junior, Eduardo Afonso, de Oliveira Silva, Eliane, Vessecchi, Ricardo, Peporine Lopes, Norberto, Tallarico Pupo, Mônica, da Silva Emery, Flavio, dos Santos Gonçalves, Natália, Alves dos Santos, Raquel, Jacometti Cardoso Furtado, Niege Araçari
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line; Cell Line, Tumor; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Fungi - metabolism; Human Physiology; Humans; Inhibitory Concentration 50; Medical Biochemistry; Mucor - metabolism; Naphthoquinones - administration & dosage; Naphthoquinones - metabolism; Naphthoquinones - pharmacology; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-016-0337-2

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 (IC 50 ) values of these β-lapachone metabolites were 33- to 52-fold greater than IC 50 values of β-lapachone. Conclusions The cytotoxic activity of β-lapachone in vivo may be reduced due to its swift conversion in blood.