[Targeting tumor hypoxia in combined therapeutic strategies in breast and ovarian cancer].

Abstract

Tumor hypoxia is a major driver of tumor progression and metastasis. Hypoxic adaptation is regulated by hypoxiainducible factor-1 (HIF-1), which controls the transcription of genes promoting malignant behavior. HIF-1 inhibitors have failed as monotherapies in clinical trials, highlighting the need for combination-based strategies. This study aimed to develop hypoxia-targeted combination therapies for breast and ovarian cancers. Using established in vitro and in vivo hypoxia models, we evaluated acriflavine, a HIF-1 inhibitor, in combination with paclitaxel and an epithelial-mesenchymal transition targeting agent. Acriflavine exerted potent antiproliferative effects, particularly in triple-negative breast cancer cell lines, and proteomic profiling indicated modulation of migration, proliferation, and cellular metabolism. The acriflavine-paclitaxel combination showed synergistic antitumor and antimetastatic activity, which was further enhanced by rolipram. Overall, our findings support hypoxia-targeted combination approaches and provide a biological rationale for combining HIF-1 inhibition with immune checkpoint blockade in breast cancer.