title: Differential effects of methoxyamine on doxorubicin cytotoxicity and genotoxicity in MDA-MB-231 human breast cancer cells.
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.
authors: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors: Patrícia S
authors: PS
authors: Guerreiro
authors: Ana Sofia
authors: AS
authors: Fernandes
authors: João G
authors: JG
authors: Costa
authors: Matilde
authors: M
authors: Castro
authors: Joana P
authors: JP
authors: Miranda
authors: Nuno G
authors: NG
authors: Oliveira
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000819:agonists / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048749:Cytokinesis / Q000187:drug effects; D003603:Cytotoxins / Q000819:agonists / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004317:Doxorubicin / Q000819:agonists / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006898:Hydroxylamines / Q000819:agonists / Q000494:pharmacology*; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D003603:Cytotoxins; D006898:Hydroxylamines; D009363:Neoplasm Proteins; D004317:Doxorubicin; C005214:methoxyamine; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Base excision repair; DNA repair; Doxorubicin; Methoxyamine; Micronuclei