Questionable Benefit of Melatonin for Antioxidant Pharmacologic Therapy
Authors: Albert Wölfler, Peter M. Abuja, Werner Linkesch, Konrad Schauenstein, Peter M. Liebmann, None Vijayalaxmi, Charles R. Thomas, Russel J. Reiter, Terence S. Herman
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.158 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12351615 Questionable Benefit of Melatonin for Antioxidant Pharmacologic Therapy Albert WölflerxAlbert WölflerSearch for articles by this author , Peter M. AbujaxPeter M. AbujaSearch for articles by this author , Werner LinkeschxWerner LinkeschSearch for articles by this author , Konrad SchauensteinxKonrad SchauensteinSearch for articles by this author , Peter M. LiebmannxPeter M. LiebmannSearch for articles by this author Vijayalaxmix VijayalaxmiSearch for articles by this author , Charles R. Thomas JrxCharles R. Thomas JrSearch for articles by this author , Russel J. ReiterxRussel J. ReiterSearch for articles by this author , Terence S. HermanxTerence S. HermanSearch for articles by this author Show More University of Graz, Graz, AustriaThe University of Texas Health Science Center, San Antonio, TX https://doi.org/10.1200/JCO.2002.99.158 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01102002In Reply:We thank Wölfler et al for commenting on our recent review related to melatonin and its oncostatic and antioxidant properties that appeared in the Journal of Clinical Oncology.1 The following response is provided with reference to their letter.Regarding the underlying mechanisms of melatonin’s tumor-inhibiting activity, Wölfler et al overlooked the important work of Blask et al2 who have elegantly defined, at least in part, the molecular mechanisms involved in inhibiting the proliferation of cancer cells after treatment with melatonin. Many pharmacologic agents are being used to treat cancer patients despite a lack of a thorough description and mechanistic aspects of their actions. Thus, if additional studies prove that melatonin is significantly oncostatic and improves the quality of life in humans with cancer (as has been reported3), definition of all its mechanisms before its use in the clinics may not be a requirement.Wölfler et al seem to object to referring to melatonin as an antioxidant because of a very small percentage (six of more than 800 total scientific reports) of publications that claim either its antioxidant action is weak or that pro-oxidant activity was noted. They cite in vitro studies, two of which used cancer cells and two others that reported melatonin was also an antioxidant. If melatonin is pro-oxidative in cancer cells, it would be beneficial because the cells damaged by oxidants would probably undergo apoptosis. The bottom line is, that of the numerous investigations related to the redox activity of melatonin, the vast majority of them overwhelmingly claim that melatonin reduces oxidative stress.4,5 Furthermore, compared with the other classical antioxidants (vitamins C and E), melatonin has always proven to be much more effective in vivo.6 Finally, the mechanisms of melatonin’s interaction with some oxygen-based reactants have been identified along with the products that are generated.6Wölfler et al use the word “supra-pharmacological” in regards to the amounts of melatonin normally given to combat oxidative damage. The precise meaning of this term and how it is distinguished from pharmacologic is not apparent. When does a dose of a pharmacologic agent become suprapharmacologic? Any antioxidant must be given in pharmacologic doses to reduce free radical damage under conditions of elevated oxidative stress, eg, ischemia perfusion injury, lipopolysachharide toxicity, toxin exposure, and so on.4,5 In fact, the reason oxidative damage occurs in these cases is that the all physiologic antioxidants combined, which naturally exist at the cellular level, are incapable of preventing the damage because the endogenous antioxidative defense system is overwhelmed by the large number of free radicals generated. Thus, any antioxidant (melatonin, vitamins C and E, and so on) must be given in a pharmacologic dose, or if Wölfler et al prefer, in suprapharmacologic amounts, under conditions of massive oxidative stress.Wölfler et al make an error in their claims as to what constitutes physiologic levels of melatonin. They note that melatonin levels in the serum are in the picomolar range (actually low nanomolar range at night) and assume that melatonin levels throughout the body are in the same range. It is well documented that melatonin levels in body fluids are not in equilibrium; melatonin concentrations in CSF, bile, and likely in some cells and organelles are orders of magnitude above those in the serum.7-10 Thus, serum melatonin levels are an inappropriate criterion to use to judge its concentrations in other body fluids and cells.11 Furthermore, pinealectomy (which lowers endogenous melatonin concentrations) exaggerates the level of free radical damage, indicating that physiologic levels of melatonin reduce the amount of oxidative damage, even under conditions of extreme oxidative stress.12Wölfler et al may have also assumed that the antioxidant activity of melatonin is exclusively related to its direct free radical scavenging activity. Although the actions of melatonin as a free radical scavenger are receptor independent, melatonin also stimulates a number of antioxidant enzymes, including increasing the synthesis of glutathione,13 an important intracellular antioxidant. Moreover, melatonin also acts synergistically with other classical antioxidants.14 The actions of melatonin on antioxidant enzymes are likely receptor mediated, and physiologic levels of melatonin (even in the blood) are in the range of the Kd of the known melatonin receptors. If Wölfler et al deny the antioxidant actions of melatonin, they must come up with an alternative explanation for its ability to markedly reduce oxidative stress, particularly, in in vivo situations. A search of the published literature will readily identify the hundreds of reports (more than 800) documenting melatonin’s efficacy in reducing oxidative damage, especially in vivo. What is important in science is the preponderance of the published evidence. Even clinical reports are beginning to appear documenting melatonin’s ability to reduce free radical damage in humans.15 In fact, the Radiation Therapy Oncology Group protocol BR-0119 is a randomized phase II clinical trial of whole-brain radiotherapy and morning versus evening melatonin (20 mg dose) in Radiation Therapy Oncology Group recursive partitioning analysis of class II patients with brain metastases. This translational research clinical trial is an attempt to further define the utility of this compound in the clinical oncology arena.It is always possible to find a few exceptional reports that question the majority. Indeed, vitamins C and E have been shown to be strongly pro-oxidant in many studies, yet, few question their antioxidant potential.1. Vijayalaxmi , Thomas CR Jr, Reiter RJ, et al: Melatonin: From basic research to cancer treatment clinics. J Clin Oncol 20:: 2575,2002-2601, Link, Google Scholar2. Blask DE, Sauer A, Dauchy RT: Melatonin as a chronobiotic/anticancer agent: Cellular, biochemical and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Topics Med Chem 2:: 113,2002-132, Crossref, Medline, Google Scholar3. Lissoni P: Is there a role for melatonin in supportive care? Support Care Cancer 10:: 110,2002-118, Crossref, Medline, Google Scholar4. Reiter RJ: Oxidative damage in the central nervous system: Protection by melatonin. Prog Neurobiol 56:: 359,1990-384, Google Scholar5. Reiter RJ, Tan DX, Manchester LC, et al: Antioxidant capacity of melatonin, in Cadenas E, Packer L, eds: Handbook of Antioxidants ( ed 2 ). New York NY, Marcel Dekker, pp 565,2002,-613 Google Scholar6. Tan DX, Reiter RJ, Manchester LC, et al: Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Topics Med Chem 2:: 181,2002-198, Crossref, Medline, Google Scholar7. Skinner DC, Malpeux B: High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology 140:: 4399,1999-4405, Crossref, Medline, Google Scholar8. Tan DX, Manchester LC, Reiter RJ, et al: High physiological levels of melatonin in the bile of mammals. Life Sci 65:: 2523,1999-2529, Crossref, Medline, Google Scholar9. Tan DX, Manchester LC, Reiter RJ, et al: Identification of highly elevated levels of melatonin in bone marrow: Its origin and significance. Biochem Biophy Acta 1472:: 206,1999-214, Crossref, Medline, Google Scholar10. Martin M, Macias M, Escames G, et al: Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress. FASEB J 14:: 1677,2000-1679, Crossref, Medline, Google Scholar11. Reiter RJ, Tan DX: Role of CSF in the transport of melatonin. J Pineal Res 33:: 61,,2002 Crossref, Medline, Google Scholar12. Manev H, Uz T, Kharlamov A, et al: Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J 10:: 1546,1996-1551, Crossref, Medline, Google Scholar13. Urata Y, Honma S, Goto S, et al: Melatonin induces gamma-glutamyl cysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Rad Biol Med 27:: 838,1999-847, Crossref, Medline, Google Scholar14. Gitto E, Tan DX, Reiter RJ, et al: Individual and synergistic actions of melatonin: Studies with vitamin E, vitamin C, glutathione and desfemoxamine in liver homogenates. J Pharm Pharmacol 53:: 1393,2001-1401, Crossref, Medline, Google Scholar15. Gitto E, Karbownick M, Reiter RJ, et al: Effects of melatonin in septic newborns. Pediat Res 50:: 756,2001-760, Crossref, Medline, Google Scholar