Open Access

REVIEW

Mechanistic Insights into the Role of Melatonin in Cancer Cell Chemoresistance

Russel J. Reiter^1,*, Ramaswamy Sharma^2,*, Walter Manucha³, Walter Balduini⁴, Doris Loh⁵, Demetrios A. Spandidos⁶, Alejandro Romero⁷, Vasiliki E. Georgakopoulou⁸, Wei Zhu⁹

1 Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX 78229, USA
2 Applied Biomedical Sciences, University of the Incarnate Word, School of Osteopathic Medicine, San Antonio, TX 78209, USA
3 Instituto de Medicina y Biologia Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Mendoza, 5500, Argentina
4 Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, 61029, Italy
5 Independent Researcher, Marble Falls, TX 78654, USA
6 Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion, 71003, Greece
7 Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, 28040, Spain
8 Department of Pathophysiology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, 11527, Greece
9 SCI Research Institute, Jericho, New York, NY 11753, USA

* Corresponding Authors: Russel J. Reiter. Email: ; Ramaswamy Sharma. Email:

(This article belongs to the Special Issue: Melatonin and Mitochondria: Exploring New Frontiers)

BIOCELL 2025, 49(11), 2033-2067. https://doi.org/10.32604/biocell.2025.067661

Received 09 May 2025; Accepted 23 July 2025; Issue published 24 November 2025

Abstract

The development of cancer cell resistance to conventional treatments continues to be a major obstacle in the successful treatment of tumors of many types. The discovery of a highly efficient direct and indirect free radical scavenger, melatonin, in the mitochondrial matrix may be a factor in determining both the occurrence of cancer cell drug insensitivity as well as radioresistance. This relates to two of the known hallmarks of cancer, i.e., exaggerated free radical generation in the mitochondria and the development of Warburg type metabolism (glycolysis). The hypothesis elaborated in this report assumes that the high oxidative environment in the mitochondria contributes to a depression of local melatonin levels because of its overuse in neutralizing the massive amount of free radial produced. Moreover, Warburg type metabolism and chemoresistance are functionally linked and supplemental melatonin has been shown to reverse glycolysis and convert glucose processing to the type that occurs in normal cells. Since this metabolic type is a key factor in determining chemoresistance, melatonin would predictably also negate cancer drug insensitivity. The possible mechanisms by which melatonin may interfere either directly or indirectly with drug resistance are summarized in the current review.

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