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

Published on Friday, 07 November 2025

Abstract

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.

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- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day and more orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Variable Part - Chondroitin sulfate, up to 3-4 grams per day, orally);

The Di Bella's Method: Use of Melatonin since 1974 - together with others chemical compounds - in several Oncological Pathologies:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;