Guerreiro Patrícia S, Fernandes Ana Sofia, Costa João G, Castro Matilde, Miranda Joana P, Oliveira Nuno G
Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Mutat Res Genet Toxicol Environ Mutagen. 2013 Oct 9;757(2):140-7. doi: 10.1016/j.mrgentox.2013.08.003. Epub 2013 Aug 16.
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.
对DNA修复进行药理学抑制是提高抗癌药物疗效的一种有前景的方法。化疗药物阿霉素（Dox）可能部分通过引起氧化性DNA损伤发挥作用。碱基切除修复（BER）途径可修复由活性氧（ROS）诱导产生的许多DNA损伤。甲氧基胺（MX）是脱嘌呤/脱嘧啶内切酶1（APE1，一种多功能BER蛋白）的间接抑制剂。我们评估了MX对MDA-MB-231转移性乳腺癌细胞中Dox的细胞毒性和遗传毒性的影响。MX对经Dox处理的细胞的活力和增殖几乎没有影响。然而，通过胞质分裂阻滞微核试验（CBMN）评估，MX使Dox诱导的微核双核细胞频率显著增加了1.4倍（P<0.05），并且还改变了微核数量的分布。荧光探针二氢乙锭（DHE）表明Dox产生的ROS很少。总体而言，我们的结果表明，在暴露于Dox的乳腺癌细胞中抑制APE1活性会产生不同的结果，观察到对遗传毒性有敏化作用，但对细胞毒性没有。
