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© 2002 American Society for Clinical Oncology
Questionable Benefit of Melatonin for Antioxidant Pharmacologic TherapyUniversity of Graz, Graz, Austria To the Editor:In their recent extensive review on the antioxidant and oncostatic actions of melatonin, Vijayalaxmi et al1 try to provide a rationale for the design of clinical trials using melatonin (MEL) in oncological settings. Even though there are reports suggesting that MEL is oncostatic in certain malignant cell lines, some animal models, and in preliminary clinical studies, the underlying molecular mechanisms remain unknown. In this context Vijayalaxmi et al1 discuss in detail reports on antioxidant effects of MEL. However, in contrast to early reports, several subsequent studies from various groups point to a limited direct antioxidant potency of MEL in biochemical assays,2-5 cultured cells,6 and animal models7 compared with other antioxidants and even other indolic compounds, such as certain precursors and metabolites of MEL. Furthermore, recent findings even demonstrate MEL to be pro-oxidant in erythrocytes,8 in lymphocytic9 and hepatocytic cell lines,10 neuronal cells,11 isolated retinal photoreceptors,12 and cell-free biochemical systems.13 Vijayalaxmi et al cited only two8,12 of these studies and considered the concentrations of MEL necessary for pro-oxidant effects as "supra-pharmacological." However, most of the discussed antioxidant effects were seen in the same or even higher concentration range: only high micro- to low millimolar concentrations of MEL were described to exhibit a significant direct antioxidant activity. A pharmacologic and, because the naturally occurring serum concentration of MEL is in the picomolar range, a physiologic significance of its antioxidant activity is therefore highly unlikely. Furthermore, a possible antioxidant role of MEL needs to be discussed in relation to the well-established endogenous antioxidant defense components; in contrast to MEL, endogenous and dietary antioxidants, such as glutathione, urate, ascorbic acid, and vitamin E are present in high micro- to millimolar concentrations intra- and extracellularly.14 Thus, even an antioxidant activity similar to the above mentioned antioxidants—although in subcellular compartments slightly higher than plasma concentrations cannot be excluded—still would not imply a respective physiologic significance of MEL. One must not forget that MEL is a signaling molecule functioning as zeitgeber15 and exhibiting its physiologic functions in the picomolar range via specific receptors.16 Therefore, and in light of its questionable benefit as antioxidant, MEL should not be considered for antioxidant pharmacologic therapy. REFERENCES
1. Vijayalaxmi , Thomas CR Jr, Reiter RJ, et al: Melatonin: From basic research to cancer treatment clinics. J Clin Oncol 20: 2575-2601, 2002 2. Marshall KA, Reiter RJ, Poeggeler B, et al: Evaluation of the antioxidant activity of melatonin in vitro. Free Radical Biol Med 21: 307-315, 1996[CrossRef][Medline] 3. Abuja PM, Liebmann P, Hayn M, et al: Antioxidant role of melatonin in lipid peroxidation of human LDL. FEBS Lett 413: 289-293, 1997[CrossRef][Medline] 4. Livrea MA, Tesoriere L, D‘Arpa D, et al: Reaction of melatonin with lipoperoxyl radicals in phospholipid bilayers. Free Radical Biol Med 23: 706-711, 1997[CrossRef][Medline] 5. Antunes F, Barclay LRC, Ingold KU, et al: On the antioxidant activity of melatonin. Free Radical Biol Med 26: 117-128, 1999[CrossRef][Medline] 6. Wölfler A, Abuja PM, Schauenstein K, et al: N-acetylserotonin is a better extra- and intracellular antioxidant than melatonin. FEBS Lett 449: 206-210, 1999[CrossRef][Medline] 7. Morgan WW, Nelson JF: Chronic administration of pharmacological levels of melatonin does not ameliorate the MPTP-induced degeneration of the nigrostriatal pathway. Brain Res 921: 115-121, 2001[CrossRef][Medline] 8. Barsacchi R, Kusmic C, Damiani E, et al: Vitamin E consumption induced by oxidative stress in red blood cells is enhanced by melatonin and reduced by N-acetylserotonin. Free Radical Biol Med 24: 1187-1192, 1998[CrossRef][Medline] 9. Wölfler A, Caluba HC, Abuja PM, et al: Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. FEBS Lett 502: 127-131, 2001[CrossRef][Medline] 10. Osseni RA, Rat P, Bogdan A, et al: Evidence of prooxidant and antioxidant action of melatonin on human liver cell line HepG2. Life Sci 68: 387-399, 2000[CrossRef][Medline] 11. Clapp-Lilly KL, Smith MA, Perry G, et al: Melatonin acts as antioxidant and prooxidant in an organotypic slice culture model of Alzheimer’s disease. Neuroreport 12: 1277-1280, 2001[CrossRef][Medline] 12. Marchiafava L, Longoni B: Melatonin as an antioxidant in retinal photoreceptors. J Pineal Res 26: 184-189, 1999[Medline] 13. Medina-Navarro R, Duran-Reyes G, Hicks JJ: Pro-oxidating properties of melatonin in the in vitro interaction with the singlet oxygen. Endocr Res 25: 263-280, 1999[Medline] 14. Halliwell B, Gutteridge JMC: Free radicals in biology and medicine. Oxford United Kingdom, Oxford University Press, 1999
15. Arendt J: Melatonin, circadian rhythms, and sleep. N Engl J Med 343: 1114-1116, 2000 16. Reppert SM, Weaver DR: Melatonin madness. Cell 83: 1059-1062, 1995[CrossRef][Medline]
ResponseThe University of Texas Health Science Center, San Antonio, TX In 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.6 Wölfler 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.12 Wölfler 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. REFERENCES
1. Vijayalaxmi , Thomas CR Jr, Reiter RJ, et al: Melatonin: From basic research to cancer treatment clinics. J Clin Oncol 20: 2575-2601, 2002 2. 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: 113-132, 2002 3. Lissoni P: Is there a role for melatonin in supportive care? Support Care Cancer 10: 110-118, 2002[CrossRef][Medline] 4. Reiter RJ: Oxidative damage in the central nervous system: Protection by melatonin. Prog Neurobiol 56: 359-384, 1990 5. 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, 2002, pp 565-613 6. 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: 181-198, 2002
7. 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: 4399-4405, 1999 8. Tan DX, Manchester LC, Reiter RJ, et al: High physiological levels of melatonin in the bile of mammals. Life Sci 65: 2523-2529, 1999[CrossRef][Medline] 9. 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: 206-214, 1999
10. 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: 1677-1679, 2000 11. Reiter RJ, Tan DX: Role of CSF in the transport of melatonin. J Pineal Res 33: 61, 2002[CrossRef][Medline] 12. Manev H, Uz T, Kharlamov A, et al: Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J 10: 1546-1551, 1996[Abstract] 13. 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: 838-847, 1999[CrossRef][Medline] 14. 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: 1393-1401, 2001[CrossRef][Medline] 15. Gitto E, Karbownick M, Reiter RJ, et al: Effects of melatonin in septic newborns. Pediat Res 50: 756-760, 2001[Medline] This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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