The work entitled «Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells» addresses the study of DNA repair inhibitors. These compounds have been developed as potential therapeutic agents for the enhancement of the chemotherapy efficacy. In this article, we assessed the effects of methoxyamine in the cytotoxicity and genotoxicity induced by doxorubicin in MDA-MB-231 breast cancer cells. Methoxyamine is an indirect inhibitor of APE1 enzyme involved in base excision repair (BER) pathway. The results obtained pointed out to an increase of DNA lesions induced by doxorubicin in the presence of methoxyamine, suggesting that the BER inhibitor potentiates the genotoxic but not cytotoxic effects of doxorubicin.

Authors and affiliations:

Patrícia S. Guerreiro1, Ana Sofia Fernandes2,1, João G. Costa1,2, Matilde Castro1, Joana P. Miranda1 e Nuno G. Oliveira1

1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal

2. CBIOS, Universidade Lusófona Research Center for Biosciences and Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal

Abstract:

Pharmacological inhibition of DNA repair is a promising approach to increase the effectiveness of anticancer drugs. The chemotherapeutic drug doxorubicin (Dox) may act, in part, by causing oxidative DNA damage. The base excision repair (BER) pathway effects the repair of many DNA lesions induced by reactive oxygen species (ROS). Methoxyamine (MX) is an indirect inhibitor of apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional BER protein. We have evaluated the effects of MX on the cytotoxicity and genotoxicity of Dox in MDA-MB-231 metastatic breast cancer cells. MX has little effects on the viability and proliferation of Dox-treated cells. However, as assessed by the cytokinesis-block micronucleus assay (CBMN), MX caused a significant 1.4-fold increase (P< 0.05) in the frequency of micronucleated binucleated cells induced by Dox, and also altered the distribution of the numbers of micronuclei. The fluorescence probe dihydroethidium (DHE) indicated little production of ROS by Dox. Overall, our results suggest differential outcomes for the inhibition of APE1 activity in breast cancer cells exposed to Dox, with a sensitizing effect observed for genotoxicity but not for cytotoxicity.

Journal:

Mutation Research - Genetic Toxicology and Environmental Mutagenesis

Link:

http://www.sciencedirect.com/science/article/pii/S138357181300226X