APX2009 sensitizes hypoxic breast cancer cells to doxorubicin by increasing its accumulation and caspase-3/7-mediated apoptosis

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 d...

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Bibliographic Details
Published in:	Breast cancer research and treatment
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Netherlands 13-10-2024
Subjects:	Hypoxia Breast cancer APE1 Doxorubicin Apoptosis
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0167-6806 1573-7217 1573-7217
DOI:	10.1007/s10549-024-07512-6