Targeting hypoxia in combination with paclitaxel to enhance therapeutic efficacy in breast and ovarian cancer

• Published in: Biomedicine & pharmacotherapy 2024-11, Vol.180, p.117601, Article 117601
• Main Authors: Svajda, Laura, Ranđelović, Ivan, Surguta, Sára Eszter, Baranyi, Marcell, Cserepes, Mihály, Tóvári, József
• Format: Article
• Language: English
• Subjects: Acriflavine - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Combination therapy; Drug Synergism; Epithelial-Mesenchymal Transition - drug effects; Female; Humans; Hypoxia targeted therapy; Metastasis; Mice; Mice, Nude; Migration; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Tumor hypoxia; Tumor Hypoxia - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117601

The poor vascularization of solid tumors results in oxygen-deprived areas within the tumor mass. This phenomenon is defined as tumor hypoxia and is considered to be a major contributor to tumor progression in breast and ovarian cancers due to hypoxia-cascade-promoted increased metastasizing capacity. Hence, targeting hypoxia is a strategic cancer treatment approach, however, the hypoxia-modulating drugs face several limitations in monotherapies. Here, we investigated the impact of the potent hypoxia-inducible factor inhibitory compound acriflavine on tumor cell proliferation, migration, and metabolism under hypoxic conditions. We identified that acriflavine inhibited the proliferation of breast and ovarian tumor cells. To model the potential benefits of additional hypoxia response inhibition next to standard chemotherapy, we combined acriflavine with a frequently used chemotherapeutic agent, paclitaxel. In most breast and ovarian cancer cell lines used, we identified additive effects between the two drugs. The most significant findings were detected in triple-negative breast cancer cell lines, where we observed synergism. The drug combination effectively impeded tumor growth and metastasis formation in an in vivo orthotopic triple-negative breast cancer model as well. Additionally, we demonstrated that an epithelial-mesenchymal transition inhibitory drug, rolipram, combined with acriflavine and paclitaxel, notably reduced the motility of hypoxic triple-negative breast cancer cells. In conclusion, we identified novel drug combinations that can potentially combat triple-negative breast cancer by inhibiting hypoxia signaling and hindering cell migration and metastasis formation. [Display omitted] •Hypoxia-targeting drug, acriflavine enhances paclitaxel efficiency in BC and OC.•Acriflavine acts hypoxia-selectively in triple-negative breast cancer.•In vivo TNBC tumor growth is reduced by acriflavine-paclitaxel combination therapy.•Combined therapy suppresses metastasis formation.•EMT inhibition with acriflavine-paclitaxel therapy decreases TNBC cell migration.