Isatin, a monoamine oxidase inhibitor, sensitizes resistant breast cancer cells to tamoxifen <i>via</i> MAO-A/HIF1α/MMPs modulation

One of the biggest obstacles to treating breast cancer effectively is chemotherapy resistance, which emphasizes the need for innovative therapeutic approaches. An important factor in tumor progression is the mitochondrial enzyme monoamine oxidase-A (MAO-A). In the development of anticancer drugs, isatin (1<i>H</i>-indole-2,3-dione), a MAO inhibitor obtained from <i>Isatis microcarpa</i>, has shown great promise. This study assessed isatin's ability to fight resistance in tamoxifen-resistant LCC2 breast cancer cells, both by itself and in combination with tamoxifen. Chromatographic techniques were used to extract and purify isatin, which was subsequently examined for cytotoxicity, cell cycle arrest, colony formation, and migratory inhibition. Isatin and tamoxifen together dramatically decreased cell viability, prevented migration, stopped the advancement of the cell cycle, and repressed proliferation. Using qRT-PCR, gene expression analysis showed that important indicators for treatment resistance and metastasis, including MAO-A, HIF-1α, TWIST, MMP2, MMP9, and ABCB1, were downregulated. ELISA-based protein expression analyses further validated the modification of proteins linked to migration and apoptosis, including BAX, BCL2, and caspases 3, 8, and 9. The ATP-binding cassette transporter ABCB1, which is intimately linked to multidrug resistance, was similarly impacted by the isatin-tamoxifen combination. In conclusion, our findings demonstrate that isatin, alone or in combination with tamoxifen, exerts significant anticancer effects in tamoxifen-resistant breast cancer cells by promoting apoptosis, cell cycle arrest, and suppression of resistance-associated pathways. These effects may involve modulation of MAO-A and HIF-1α signaling, highlighting MAO-A as a lesser-studied but promising target in breast cancer.