de Amorim Ísis Salviano Soares, Pinheiro Daphne, da Silva Oliveira Matheus, de Sousa Rodrigues Mariana Moreno, José Julia Silva, Siqueira Priscyanne Barreto, Pires Bruno Ricardo Barreto, de Souza da Fonseca Adenilson, Mencalha Andre Luiz
Laboratório de Biologia Do Câncer, Instituto de Biologia Roberto Alcântara Gomes, Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Laboratório de Alimentos Funcionais, Instituto de Nutrição Josué de Castro, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Breast Cancer Res Treat. 2025 Feb;209(3):533-540. doi: 10.1007/s10549-024-07512-6. Epub 2024 Oct 13.
The association of targeted therapy with chemotherapy is encouraged to increase the treatment efficiency, especially in hypoxic triple-negative breast cancer. The APE1 redox activity has stood out as a potential tumor target. However, the effect of the association of the APE1 redox inhibitors with doxorubicin in hypoxia still needs to be evidenced. Therefore, our objective was to investigate the effect of the APX2009 (APE1 inhibitor) on the sensitization of breast cancer cells to doxorubicin in normoxia and hypoxia.
The WST-1 assay was used to evaluate cell viability after APX2009 and doxorubicin application under normoxia and hypoxia conditions in the MCF-7 and MDA-MB-231 cells. Apoptosis was analyzed by annexin assay and detection of caspases-3/7 activity by luminescence-based assay. The clinical association between APE1 inhibition signature and doxorubicin sensitivity was evaluated by bioinformatics analyses.
MDA-MB-231 and MCF-7 cell lines were more sensitive to APX2009 in normoxia than in hypoxia. Co-treatment with APX2009 and doxorubicin in hypoxia further decreased the viability of triple-negative MDA-MB-231 cells than treatment alone, which was accompanied by doxorubicin intracellular accumulation, and increase of apoptotic cells percentage, and caspases-3/7 activity. Moderate association was found between APE1 inhibition signature and doxorubicin sensitivity in the hypoxic basal subtype.
The findings suggest that APX2009 sensitizes the MDA-MB-231 cells to doxorubicin in hypoxia by doxorubicin intracellular accumulation and caspases-3/7-mediated apoptosis.
鼓励将靶向治疗与化疗联合使用以提高治疗效果，尤其是在缺氧的三阴性乳腺癌中。APE1氧化还原活性已成为一个潜在的肿瘤靶点。然而，APE1氧化还原抑制剂与阿霉素联合在缺氧条件下的效果仍需证实。因此，我们的目的是研究APX2009（一种APE1抑制剂）在常氧和缺氧条件下对乳腺癌细胞对阿霉素敏感性的影响。
采用WST-1法评估在常氧和缺氧条件下，将APX2009和阿霉素应用于MCF-7和MDA-MB-231细胞后的细胞活力。通过膜联蛋白检测和基于发光法检测caspases-3/7活性来分析细胞凋亡情况。通过生物信息学分析评估APE1抑制特征与阿霉素敏感性之间的临床相关性。
MDA-MB-231和MCF-7细胞系在常氧条件下比在缺氧条件下对APX2009更敏感。在缺氧条件下，将APX2009与阿霉素联合处理比单独处理能进一步降低三阴性MDA-MB-231细胞的活力，这伴随着阿霉素在细胞内的积累、凋亡细胞百分比的增加以及caspases-3/7活性的增强。在缺氧的基底亚型中，发现APE1抑制特征与阿霉素敏感性之间存在中度相关性。
研究结果表明，APX2009通过阿霉素在细胞内的积累以及caspases-3/7介导的凋亡，使MDA-MB-231细胞在缺氧条件下对阿霉素敏感。
