Melatonin Overcomes Cancer Multidrug Resistance by Downregulating ABCB1 Expression and Modulating Mitochondrial Function

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. A critical factor contributing to MDR is overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1. Novel alternative therapeutic strategies are needed to overcome resistance associated with ABC transporters. In the present study, we aimed to elucidate the mechanisms by which melatonin overcomes ABCB1-mediated MDR in cancer cells, with a focus on mitochondrial function. We analyzed the effects of melatonin (1 mM) on head and neck squamous cell carcinoma cell lines (CAL 27 and SCC-9) overexpressing ABCB1 and exhibiting increased resistance to cisplatin (CDDP) compared to their parental cells. To further validate the role of melatonin in reversing ABCB1-mediated MDR, we also evaluated its effects on doxorubicin-resistant MCF-7 breast cancer cells. We further examined the potential of melatonin to overcome MDR in CAL 27 xenografted mice. Here, we report that melatonin treatment specifically triggered reactive oxygen species (ROS) production in mitochondria and weakened chemoresistance. ROS oxidized NADH into NAD⁺, and limiting the availability of ATP for efflux pump activity. Additionally, melatonin decreased the number of mitochondria localized near the nucleus instead of the cytoplasm and downregulated ABCB1 expression. Intratumoral administration of melatonin effectively overcame CDDP resistance in CAL 27/ABCB1 xenografts, significantly reducing tumor volume and promoting apoptosis. These findings demonstrate that melatonin enhances chemosensitivity in ABCB1-overexpressing cells by modulating mitochondrial metabolism, redox balance, and ABCB1 expression, highlighting its potential as an adjuvant therapy to overcome MDR.