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.
