MINI-REVIEW
Potential use of melatonin in skin cancer treatment: A review of current biological evidence
Mohammad Hossein Pourhanifeh,
Mostafa Mahdavinia,
Russel J. Reiter,
Zatollah Asemi,
Mohammad Hossein Pourhanifeh
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I. R. Iran
Search for more papers by this authorMostafa Mahdavinia
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, I. R. Iran
Search for more papers by this authorRussel J. Reiter
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Zatollah Asemi
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I. R. Iran
Correspondence Zatollah Asemi, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Ghotbe Ravandi Boulevard, Kashan 8715988141, I. R. Iran. Email: [email protected]
Search for more papers by this author
Mohammad Hossein Pourhanifeh,
Mostafa Mahdavinia,
Russel J. Reiter,
Zatollah Asemi,
Mohammad Hossein Pourhanifeh
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I. R. Iran
Search for more papers by this authorMostafa Mahdavinia
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, I. R. Iran
Search for more papers by this authorRussel J. Reiter
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Zatollah Asemi
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I. R. Iran
Correspondence Zatollah Asemi, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Ghotbe Ravandi Boulevard, Kashan 8715988141, I. R. Iran. Email: [email protected]
Search for more papers by this authorAbstract
Skin cancer, particularly melanoma, is a leading cause of death worldwide. The therapeutic methods for this malignancy are not effective, and due to the side effects of these treatments, applying an appropriate alternative or complementary treatment is important. According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti-inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor-erythroid 2 p45-related factor 2 and others. Thus, adding melatonin to chemo- and radiotherapy may have synergistic therapeutic effects and increase the survival time in patients with skin cancer. Few clinical studies have evaluated the efficacy of melatonin in skin cancer. Based on the related mechanisms, this review discusses about how melatonin may improve outcomes in skin cancer patients.
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
REFERENCES
- Abdul-Karim, R., & Cowey, L. (2017). Challenging the standard of care in advanced melanoma: Focus on pembrolizumab. Cancer Management and Research, 9, 433–442. https://doi.org/10.2147/cmar.s92546
- Altun, A., & Ugur-Altun, B. (2007). Melatonin: Therapeutic and clinical utilization. International Journal of Clinical Practice, 61(5), 835–845. https://doi.org/10.1111/j.1742-1241.2006.01191.x
- Andor, N., Graham, T. A., Jansen, M., Xia, L. C., Aktipis, C. A., Petritsch, C., … Maley, C. C. (2016). Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nature Medicine, 22(1), 105–113. https://doi.org/10.1038/nm.3984
- Arad, S., Konnikov, N., Goukassian, D. A., & Gilchrest, B. A. (2007). Quantification of inducible SOS-like photoprotective responses in human skin. Journal of Investigative Dermatology, 127(11), 2629–2636. https://doi.org/10.1038/sj.jid.5700893
- Asnaghi, L., Calastretti, A., Bevilacqua, A., D'Agnano, I., Gatti, G., Canti, G., … Nicolin, A. (2004). Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene, 23(34), 5781–5791. https://doi.org/10.1038/sj.onc.1207698
- Atessahin, A., Sahna, E., Turk, G., Ceribasi, A. O., Yilmaz, S., Yuce, A., & Bulmus, O. (2006). Chemoprotective effect of melatonin against cisplatin-induced testicular toxicity in rats. Journal of Pineal Research, 41(1), 21–27. https://doi.org/10.1111/j.1600-079X.2006.00327.x
- Blask, D. E., Dauchy, R. T., & Sauer, L. A. (2005). Putting cancer to sleep at night: The neuroendocrine/circadian melatonin signal. Endocrine, 27(2), 179–188. https://doi.org/10.1385/endo:27:2:179
- Brash, D. E., Ziegler, A., Jonason, A. S., Simon, J. A., Kunala, S., & Leffell, D. J. (1996). Sunlight and sunburn in human skin cancer: P53, apoptosis, and tumor promotion. The Journal of Investigative Dermatology. Symposium Proceedings, 1(2), 136–142.
- Bubenik, G. A., & Smith, P. S. (1987). Circadian and circannual rhythms of melatonin in plasma of male white-tailed deer and the effect of oral administration of melatonin. Journal of Experimental Zoology, 241(1), 81–89. https://doi.org/10.1002/jez.1402410110
- Cain, K., Bratton, S. B., & Cohen, G. M. (2002). The Apaf-1 apoptosome: A large caspase-activating complex. Biochimie, 84(2-3), 203–214.
- Canonico, B., Luchetti, F., Ambrogini, P., Arcangeletti, M., Betti, M., Cesarini, E., … Papa, S. (2013). Pharmacological doses of melatonin induce alterations in mitochondrial mass and potential, bcl-2 levels and K + currents in UVB-exposed U937 cells. Cell Biology International, 37(3), 213–226. https://doi.org/10.1002/cbin.10030
- Carrillo-Vico, A., Calvo, J. R., Abreu, P., Lardone, P. J., García-Mauriño, S., Reiter, R. J., & Guerrero, J. M. (2004). Evidence of melatonin synthesis by human lymphocytes and its physiological significance: Possible role as intracrine, autocrine, and/or paracrine substance. FASEB Journal, 18(3), 537–539. https://doi.org/10.1096/fj.03-0694fje
- Castelli, C., Ciupitu, A. M., Rini, F., Rivoltini, L., Mazzocchi, A., Kiessling, R., & Parmiani, G. (2001). Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Research, 61(1), 222–227.
- Catalá, A., Zvara, Á., Puskás, L. G., & Kitajka, K. (2007). Melatonin-induced gene expression changes and its preventive effects on adriamycin-induced lipid peroxidation in rat liver. Journal of Pineal Research, 42(1), 43–49. https://doi.org/10.1111/j.1600-079X.2006.00354.x
- Esposito, E., & Cuzzocrea, S. (2010). Antiinflammatory activity of melatonin in central nervous system. Current Neuropharmacology, 8(3), 228–242. https://doi.org/10.2174/157015910792246155
- Esposito, E., Iacono, A., Muià, C., Crisafulli, C., Mattace Raso, G., Bramanti, P., … Cuzzocrea, S. (2008). Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. Journal of Pineal Research, 44(1), 78–87. https://doi.org/10.1111/j.1600-079X.2007.00492.x
- Fischer, T. W., & Elsner, P. (2001). The antioxidative potential of melatonin in the skin. Current Problems in Dermatology, 29, 165–174.
- Fischer, T. W., Scholz, G., Knoll, B., Hipler, U. C., & Elsner, P. (2004). Melatonin suppresses reactive oxygen species induced by UV irradiation in leukocytes. Journal of Pineal Research, 37(2), 107–112. https://doi.org/10.1111/j.1600-079X.2004.00142.x
- Fischer, T. W., Zmijewski, M. A., Wortsman, J., & Slominski, A. (2008). Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes. Journal of Pineal Research, 44(4), 397–407. https://doi.org/10.1111/j.1600-079X.2007.00542.x
- Fischer, T. W., Zmijewski, M. A., Zbytek, B., Sweatman, T. W., Slominski, R. M., Wortsman, J., & Slominski, A. (2006). Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines. International Journal of Oncology, 29(3), 665–672.
- Fu, S., Wu, H., Zhang, H., Lian, C. G., & Lu, Q. (2017). DNA methylation/hydroxymethylation in melanoma. Oncotarget, 8(44), 78163–78173. https://doi.org/10.18632/oncotarget.18293
- Goswami, S., & Haldar, C. (2015). Melatonin as a possible antidote to UV radiation induced cutaneous damages and immune-suppression: An overview. Journal of Photochemistry and Photobiology. B, Biology, 153, 281–288. https://doi.org/10.1016/j.jphotobiol.2015.10.006
- Grzywa, T. M., Paskal, W., & Włodarski, P. K. (2017). Intratumor and intertumor heterogeneity in melanoma. Translational Oncology, 10(6), 956–975. https://doi.org/10.1016/j.tranon.2017.09.007
- Guengerich, F. P. (2007). Cytochrome p450 and chemical toxicology. Chemical Research in Toxicology, 21(1), 70–83.
- Guerrero, J., & Reiter, R. (2002). Melatonin-immune system relationships. Current Topics in Medicinal Chemistry, 2(2), 167–179.
- Guzhova, I., & Margulis, B. (2006). Hsp70 chaperone as a survival factor in cell pathology. International Review of Cytology, 254, 101–149. https://doi.org/10.1016/s0074-7696(06)54003-3
- Hernando, B., Ibarrola-Villava, M., Fernandez, L. P., Peña-Chilet, M., Llorca-Cardeñosa, M., Oltra, S. S., … Ribas, G. (2016). Sex-specific genetic effects associated with pigmentation, sensitivity to sunlight, and melanoma in a population of Spanish origin. Biology of Sex Differences, 7, 17. https://doi.org/10.1186/s13293-016-0070-1
- Huo, X., Wang, C., Yu, Z., Peng, Y., Wang, S., Feng, S., … Ma, X. (2017). Human transporters, PEPT 1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential. Journal of Pineal Research, 62(4), e12390.
- Isoherranen, K., Sauroja, I., Jansen, C., & Punnonen, K. (1999). UV irradiation induces downregulation of bcl-2 expression in vitro and in vivo. Archives of Dermatological Research, 291(4), 212–216.
- Jiang, W., Tian, X., Wang, Y., Sun, Z., Dong, P., Wang, C., … Ma, X. (2016). The natural anthraquinones from Rheum palmatum induced the metabolic disorder of melatonin by inhibiting human CYP and SULT enzymes. Toxicology Letters, 262, 27–38.
- Jonak, C., Klosner, G., & Trautinger, F. (2006). Heat shock proteins in the skin. International Journal of Cosmetic Science, 28(4), 233–241. https://doi.org/10.1111/j.1467-2494.2006.00327.x
- Kanikkannan, N., Jackson, T., Sudan shaik, M., & Singh, M. (2001). Evaluation of skin sensitization potential of melatonin and nimesulide by murine local lymph node assay. European Journal of Pharmaceutical Science, 14(3), 217–220.
- Kappes, U. P., Luo, D., Potter, M., Schulmeister, K., & Rünger, T. M. (2006). Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells. Journal of Investigative Dermatology, 126(3), 667–675. https://doi.org/10.1038/sj.jid.5700093
- Keller, H. R., Zhang, X., Li, L., Schaider, H., & Wells, J. W. (2017). Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma. Oncotarget, 8(43), 75675–75686. https://doi.org/10.18632/oncotarget.18523
- Kim, C., Kim, N., Joo, H., Youm, J. B., Park, W. S., Cuong, D. V., … Han, J. (2005). Modulation by melatonin of the cardiotoxic and antitumor activities of adriamycin. Journal of Cardiovascular Pharmacology, 46(2), 200–210.
- Kim, C. H., & Yoo, Y. M. (2010). Melatonin induces apoptotic cell death via p53 in LNCaP cells. The Korean Journal of Physiology & Pharmacology, 14(6), 365–369. https://doi.org/10.4196/kjpp.2010.14.6.365
- Kim, H. S., Kim, T.-J., & Yoo, Y.-M. (2014). Melatonin combined with endoplasmic reticulum stress induces cell death via the PI3K/Akt/mTOR pathway in B16F10 melanoma cells. PLOS One, 9(3), e92627. https://doi.org/10.1371/journal.pone.0092627
- Kleszczyński, K., Tukaj, S., Kruse, N., Zillikens, D., & Fischer, T. W. (2013). Melatonin prevents ultraviolet radiation-induced alterations in plasma membrane potential and intracellular pH in human keratinocytes. Journal of Pineal Research, 54(1), 89–99. https://doi.org/10.1111/j.1600-079X.2012.01028.x
- Kleszczyński, K., Zwicker, S., Tukaj, S., Kasperkiewicz, M., Zillikens, D., Wolf, R., & Fischer, T. W. (2015). Melatonin compensates silencing of heat shock protein 70 and suppresses ultraviolet radiation-induced inflammation in human skin ex vivo and cultured keratinocytes. Journal of Pineal Research, 58(1), 117–126. https://doi.org/10.1111/jpi.12197
- Kong, F., Wang, H., Guo, J., Peng, M., Ji, H., Yang, H., & Li, S. (2016). Hsp70 suppresses apoptosis of BRL cells by regulating the expression of Bcl-2, cytochrome C, and caspase 8/3. In Vitro Cellular & Developmental Biology-Animal, 52(5), 568–575. https://doi.org/10.1007/s11626-016-0005-5
- Kumar, C. A., & Das, U. N. (2000). Effect of melatonin on two stage skin carcinogenesis in Swiss mice. Medical Science Monitor, 6(3), 471–475.
- Lerchl, A., & Schlatt, S. (1993). Influence of photoperiod on pineal melatonin synthesis, fur color, body weight, and reproductive function in the female Djungarian hamster, Phodopus sungorus. Neuroendocrinology, 57(2), 359–364. https://doi.org/10.1159/000126380
- Lin, A., & Karin, M. (2003). NF-kappaB in cancer: A marked target. Seminars in Cancer Biolog, 13(2), 107–114.
- Lincoln, G. A. (2006). Decoding the nightly melatonin signal through circadian clockwork. Molecular and Cellular Endocrinology, 252(1-2), 69–73. https://doi.org/10.1016/j.mce.2006.03.006
- Lissoni, P. (2002). Is there a role for melatonin in supportive care? Supportive Care in Cancer, 10(2), 110–116. https://doi.org/10.1007/s005200100281
- Lissoni, P., Barni, S., Mandalà, M., Ardizzoia, A., Paolorossi, F., Vaghi, M., … Tancini, G. (1999). Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. European Journal of Cancer, 35(12), 1688–1692.
- Lissoni, P., Fumagalli, L., Paolorossi, F., Rovelli, F., Roselli, M. G., & Maestroni, G. J. (1997). Anticancer neuroimmunomodulation by pineal hormones other than melatonin: Preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. Journal of Biological Regulators and Homeostatic Agents, 11(3), 119–122.
- Lissoni, P., Vaghi, M., Ardizzoia, A., Malugani, F., Fumagalli, E., Bordin, V., & Tancini, G. (2002). A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. In Vivo, 16(2), 93–96.
- De Maio, A. (2014). Extracellular Hsp70: Export and function. Current Protein & Peptide Science, 15(3), 225–231.
- Malhotra, S., Sawhney, G., & Pandhi, P. (2004). The therapeutic potential of melatonin: A review of the science. MedGenMed, 6(2), 46.
- Man'cheva, T. A., Demidov, D. V., Plotnikova, N. A., Kharitonova, T. V., Pashkevich, I. V., & Anisimov, V. N. (2011). Melatonin and metformin inhibit skin carcinogenesis and lipid peroxidation induced by benz(a)pyrene in female mice. Bulletin of Experimental Biology and Medicine, 151(3), 363–365.
- Marek, Ł. (2013). The role of the apoptosome in the activation of procaspase-9. Postępy Higieny i Medycyny Doświadczalnej (Online), 67, 54–64.
- Mauriz, J. L., Collado, P. S., Veneroso, C., Reiter, R. J., & González-Gallego, J. (2013). A review of the molecular aspects of melatonin's anti-inflammatory actions: Recent insights and new perspectives. Journal of Pineal Research, 54(1), 1–14. https://doi.org/10.1111/j.1600-079X.2012.01014.x
- Morimoto, R. I., & Santoro, M. G. (1998). Stress-inducible responses and heat shock proteins: New pharmacologic targets for cytoprotection. Nat Biotech., 16(9), 833–838. https://doi.org/10.1038/nbt0998-833
- Nebert, D. W., Wikvall, K., & Miller, W. L. (2013). Human cytochromes P450 in health and disease. Philosophical Transactions of the Royal Society, B: Biological Sciences, 368(1612), 20120431–20120431.
- Ozben, T. (2015). Antioxidant supplementation on cancer risk and during cancer therapy: An update. Current Topics in Medicinal Chemistry, 15(2), 170–178.
- Palli, D., Trallori, G., Saieva, C., Tarantino, O., Edili, E., D'Albasio, G., … Masala, G. (1998). General and cancer specific mortality of a population based cohort of patients with inflammatory bowel disease: The Florence Study. Gut, 42(2), 175–179.
- Pariente, R., Pariente, J. A., Rodríguez, A. B., & Espino, J. (2016). Melatonin sensitizes human cervical cancer H e L a cells to cisplatin-induced cytotoxicity and apoptosis: Effects on oxidative stress and DNA fragmentation. Journal of Pineal Research, 60(1), 55–64.
- Pfeifer, G. P. (2015). How the environment shapes cancer genomes. Current Opinion in Oncology, 27(1), 71–77. https://doi.org/10.1097/cco.0000000000000152
- Raimondi, S., Sera, F., Gandini, S., Iodice, S., Caini, S., Maisonneuve, P., & Fargnoli, M. C. (2008). MC1R variants, melanoma and red hair color phenotype: A meta-analysis. International Journal of Cancer, 122(12), 2753–2760. https://doi.org/10.1002/ijc.23396
- Reiter, R. J., Tan, D., Kim, S. J., Manchester, L. C., Qi, W., Garcia, J. J., … Rouvier-Garay, V. (1999). Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mechanisms of Ageing and Development, 110(3), 157–173.
- Reiter, R. J., Tan, D. X., Manchester, L. C., & El-Sawi, M. R. (2002). Melatonin reduces oxidant damage and promotes mitochondrial respiration: Implications for aging. Annals of the New York Academy of Sciences, 959, 238–250.
- Roberts, J. E., F. wiechmann, A., & Hu, D. N. (2000). Melatonin receptors in human uveal melanocytes and melanoma cells. Journal of Pineal Research, 28(3), 165–171.
- Shapiro, C. L. (2016). Highlights of recent findings on quality-of-life management for patients with cancer and their survivors. JAMA Oncology, 2(11), 1401–1402.
- Slominski, A., & Pruski, D. (1993). Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells. Experimental Cell Research, 206(2), 189–194. https://doi.org/10.1006/excr.1993.1137
- Slominski, A., Fischer, T. W., Zmijewski, M. A., Wortsman, J., Semak, I., Zbytek, B., … Tobin, D. J. (2005). On the role of melatonin in skin physiology and pathology. Endocrine, 27(2), 137–148. https://doi.org/10.1385/endo:27:2:137
- Slominski, A., Pisarchik, A., Semak, I., Sweatman, T., Wortsman, J., Szczesniewski, A., … Johansson, O. (2002). Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB Journal, 16(8), 896–898. https://doi.org/10.1096/fj.01-0952fje
- Slominski, A., Pisarchik, A., Zbytek, B., Tobin, D. J., Kauser, S., & Wortsman, J. (2003). Functional activity of serotoninergic and melatoninergic systems expressed in the skin. Journal of Cellular Physiology, 196(1), 144–153. https://doi.org/10.1002/jcp.10287
- Su, S. C., Hsieh, M. J., Yang, W. E., Chung, W. H., Reiter, R. J., & Yang, S. F. (2017). Cancer metastasis: Mechanisms of inhibition by melatonin. Journal of Pineal Research, 62(1), e12370. https://doi.org/10.1111/jpi.12370
- Tan, D., Reiter, R., Manchester, L., Yan, M., El-Sawi, M., Sainz, R., … Hardelan, R. (2002). Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Current Topics in Medicinal Chemistry, 2(2), 181–197.
- Tian, X., Huo, X., Dong, P., Wu, B., Wang, X., Wang, C., … Ma, X. (2015). Sulfation of melatonin: Enzymatic characterization, differences of organs, species and genders, and bioactivity variation. Biochemical Pharmacology, 94(4), 282–296.
- Tirado, O. M., Mateo-Lozano, S., & Notario, V. (2005). Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax: Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity. Oncogene, 24(20), 3348–3357. https://doi.org/10.1038/sj.onc.1208471
- Trautinger, F. (2001). Heat shock proteins in the photobiology of human skin. Journal of Photochemistry and Photobiology. B, Biology, 63(1-3), 70–77.
- Turcotte, L. M., Liu, Q., Yasui, Y., Arnold, M. A., Hammond, S., Howell, R. M., … Neglia, J. P. (2017). Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970–2015. Journal of the American Medical Association, 317(8), 814–824.
- Vasin, M. V., & Ushakov, I. B. (2014). Comparative efficacy and the window of radioprotection for adrenergic and serotoninergic agents and aminothiols in experiments with small and large animals. Journal of Radiation Research, 56(1), 1–10.
- Wang, Y., Jin, B., Ai, F., Duan, C., Lu, Y., Dong, T., & Fu, Q. (2012). The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: A meta-analysis of randomized controlled trials. Cancer Chemotherapy and Pharmacology, 69(5), 1213–1220.
- Waterhouse, J., Reilly, T., Atkinson, G., & Edwards, B. (2007). Jet lag: Trends and coping strategies. Lancet, 369(9567), 1117–1129. https://doi.org/10.1016/s0140-6736(07)60529-7
- Werzowa, J., Koehrer, S., Strommer, S., Cejka, D., Fuereder, T., Zebedin, E., & Wacheck, V. (2011). Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo. Journal of Investigative Dermatology, 131(2), 495–503. https://doi.org/10.1038/jid.2010.327
- Wilson, N., McArdle, A., Guerin, D., Tasker, H., Wareing, P., Foster, C. S., … Rhodes, L. E. (2000). Hyperthermia to normal human skin in vivo upregulates heat shock proteins 27, 60, 72i and 90. Journal of Cutaneous Pathology, 27(4), 176–182.
- Xie, X., White, E. P., & Mehnert, J. M. (2013). Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLOS One, 8(1), e55096. https://doi.org/10.1371/journal.pone.0055096
- Yi, C., Zhang, Y., Yu, Z., Xiao, Y., Wang, J., Qiu, H., … Deng, W. (2014). Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-kappaB/p300 signaling pathways. PLOS One, 9(7), e99943. https://doi.org/10.1371/journal.pone.0099943
- Yousaf, F., Seet, E., Venkatraghavan, L., Abrishami, A., & Chung, F. (2010). Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: A qualitative systematic review of randomized trials. Anesthesiology, 113(4), 968–976. https://doi.org/10.1097/ALN.0b013e3181e7d626
- Yu, Z., Tian, X., Peng, Y., Sun, Z., Wang, C., Tang, N., … Ma, X. (2018). Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin-induced apoptosis in neural cancer cells. Journal of Pineal Research, 65, e12478.
- Öz, E., Erbaş, D., Sürücü, H. S., & Düzgün, E. (2006). Prevention of doxorubicin-induced cardiotoxicity by melatonin. Molecular and Cellular Biochemistry, 282(1-2), 31–37. https://doi.org/10.1007/s11010-006-1153-9
- Żmijewski, M. A., Sweatman, T. W., & Slominski, A. T. (2009). The melatonin-producing system is fully functional in retinal pigment epithelium (ARPE-19). Molecular and Cellular Endocrinology, 307(1-2), 211–216. https://doi.org/10.1016/j.mce.2009.04.010
