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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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.

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Acknowledgments

The authors are grateful to the University of São Paulo, Brazil, for providing technical support to carry out the experiments and to Dayana Rubio Gouvea and José Carlos Tomaz (NPPNS-FCFRP/USP) for mass spectrometry analyses.

Author information

Authors and Affiliations

  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

    Camila Raquel Paludo, Eduardo Afonso da Silva-Junior, Eliane de Oliveira Silva, Mônica Tallarico Pupo, Flavio da Silva Emery & Niege Araçari Jacometti Cardoso Furtado

  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

    Ricardo Vessecchi

  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

    Ricardo Vessecchi & Norberto Peporine Lopes

  4. Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Av. Armando de Sales Oliveira, 201, Franca, São Paulo, 14404-600, Brazil

    Natália dos Santos Gonçalves & Raquel Alves dos Santos

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  1. Camila Raquel Paludo
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  2. Eduardo Afonso da Silva-Junior
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  3. Eliane de Oliveira Silva
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  6. Mônica Tallarico Pupo
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  7. Flavio da Silva Emery
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  8. Natália dos Santos Gonçalves
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  9. Raquel Alves dos Santos
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  10. Niege Araçari Jacometti Cardoso Furtado
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Corresponding author

Correspondence to Niege Araçari Jacometti Cardoso Furtado.

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Funding

“São Paulo Research Foundation” (FAPESP Grants 2011/21700-5, 2011/01303-1 and 2009/51812-0), “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq) and “Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES).

Conflict of interest

The authors declare that they have no conflict of interest.

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Paludo, C.R., da Silva-Junior, E.A., de Oliveira Silva, E. et al. Inactivation of β-Lapachone Cytotoxicity by Filamentous Fungi that Mimic the Human Blood Metabolism. Eur J Drug Metab Pharmacokinet 42, 213–220 (2017). https://doi.org/10.1007/s13318-016-0337-2

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