Mechanistic Insights into the Role of Melatonin in Cancer Cell Chemoresistance

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.