{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:07:42Z","timestamp":1791324462877,"version":"4.3.1"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T00:00:00Z","timestamp":1673654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001287","name":"Elsa U. Pardee Foundation","doi-asserted-by":"publisher","award":["671432"],"award-info":[{"award-number":["671432"]}],"id":[{"id":"10.13039\/100001287","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001287","name":"Elsa U. Pardee Foundation","doi-asserted-by":"publisher","award":["ES033806"],"award-info":[{"award-number":["ES033806"]}],"id":[{"id":"10.13039\/100001287","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH R21","award":["671432"],"award-info":[{"award-number":["671432"]}]},{"name":"NIH R21","award":["ES033806"],"award-info":[{"award-number":["ES033806"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Melanoma is the most aggressive type of skin cancer, with a greater risk of metastasis and a higher prevalence and mortality rate. This cancer type has been demonstrated to develop resistance to the known treatment options such as conventional therapeutic agents and targeted therapy that are currently being used as the standard of care. Drug repurposing has been explored as a potential alternative treatment strategy against disease pathophysiologies, including melanoma. To that end, multiple studies have suggested that melatonin produced by the pineal gland possesses anti-proliferative and oncostatic effects in experimental melanoma models. The anticarcinogenic activity of melatonin is attributed to its ability to target a variety of oncogenic signaling pathways, including the MAPK pathways which are involved in regulating the behavior of cancer cells, including cell survival and proliferation. Additionally, preclinical studies have demonstrated that melatonin in combination with chemotherapeutic agents exerts synergistic effects against melanoma. The goal of this review is to highlight the mechanistic insights of melatonin as a monotherapy or combinational therapy for melanoma treatment.<\/jats:p>","DOI":"10.3390\/medsci11010009","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T05:30:07Z","timestamp":1673847007000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Melatonin as a Repurposed Drug for Melanoma Treatment"],"prefix":"10.3390","volume":"11","author":[{"given":"Rachana","family":"Pathipaka","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Thyagarajan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi P.","family":"Sahu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1080\/15384047.2019.1640032","article-title":"Current state of melanoma diagnosis and treatment","volume":"20","author":"Davis","year":"2019","journal-title":"Cancer Biol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101030","DOI":"10.1016\/j.cpsurg.2021.101030","article-title":"Malignant melanoma: Evolving practice management in an era of increasingly effective systemic therapies","volume":"59","author":"Newcomer","year":"2022","journal-title":"Curr. Probl. Surg."},{"key":"ref_3","first-page":"1071","article-title":"Cutaneous melanoma: From pathogenesis to therapy","volume":"52","author":"Leonardi","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(18)31559-9","article-title":"Melanoma","volume":"392","author":"Schadendorf","year":"2018","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.suc.2019.09.005","article-title":"Epidemiology and Risk Factors of Melanoma","volume":"100","author":"Carr","year":"2019","journal-title":"Surg. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/phpp.12329","article-title":"Mechanisms and prevention of UV-induced melanoma","volume":"34","author":"Sample","year":"2017","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.soncn.2016.05.005","article-title":"Ultraviolet Radiation Exposure and Its Impact on Skin Cancer Risk","volume":"32","author":"Watson","year":"2016","journal-title":"Semin. Oncol. Nurs."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jso.25604","article-title":"Melanoma","volume":"120","author":"Scoggins","year":"2019","journal-title":"J. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.stem.2017.09.001","article-title":"Melanocyte Stem Cell Activation and Translocation Initiate Cutaneous Melanoma in Response to UV Exposure","volume":"21","author":"Moon","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fmolb.2020.00154","article-title":"Current State of Target Treatment in BRAF Mutated Melanoma","volume":"7","author":"Tanda","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13046-019-1036-z","article-title":"Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS\/hTERT signaling and cancer-stem cell traits","volume":"38","author":"Hao","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1002\/cncr.31345","article-title":"Melanoma: What do all the mutations mean?","volume":"124","author":"Davis","year":"2018","journal-title":"Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Heppt, M.V., Siepmann, T., Engel, J., Schubert-Fritschle, G., Eckel, R., Mirlach, L., Kirchner, T., Jung, A., Gesierich, A., and Ruzicka, T. (2017). Prognostic significance of BRAF and NRAS mutations in melanoma: A German study from routine care. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3529-5"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1002\/cncr.30593","article-title":"Somatic driver mutations in melanoma","volume":"123","author":"Reddy","year":"2017","journal-title":"Cancer"},{"key":"ref_15","first-page":"7043","article-title":"BRAF, NRAS and C-KIT Advanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival","volume":"37","author":"Ponti","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/bjd.15436","article-title":"Beyond the BRAF V 600E hotspot: Biology and clinical implications of rare BRAF gene mutations in melanoma patients","volume":"177","author":"Richtig","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/modpathol.2017.104","article-title":"Molecular testing for BRAF mutations to inform melanoma treatment decisions: A move toward precision medicine","volume":"31","author":"Cheng","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.bbcan.2019.02.002","article-title":"Many ways to resistance: How melanoma cells evade targeted therapies","volume":"1871","author":"Kozar","year":"2019","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_19","first-page":"68","article-title":"BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients","volume":"22","author":"Mackiewicz","year":"2018","journal-title":"Contemp. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/S1470-2045(14)70301-8","article-title":"Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: A phase 1b study","volume":"15","author":"Ribas","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1056\/NEJMoa1406037","article-title":"Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma","volume":"371","author":"Long","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1056\/NEJMoa1412690","article-title":"Improved overall survival in melanoma with combined dabrafenib and trametinib","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1200\/JCO.20.00198","article-title":"Systemic Therapy for Melanoma: ASCO Guideline","volume":"38","author":"Seth","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"689","DOI":"10.2217\/fon-2020-0643","article-title":"First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: A real-world analysis","volume":"17","author":"Pavlick","year":"2021","journal-title":"Futur. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/s41416-020-01229-1","article-title":"First-line BRAF\/MEK inhibitors versus anti-PD-1 monotherapy in BRAFV600-mutant advanced melanoma patients: A propensity-matched survival analysis","volume":"124","author":"Wouters","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_26","first-page":"237","article-title":"Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma","volume":"11","author":"Kim","year":"2014","journal-title":"Cancer Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.jaad.2020.03.131","article-title":"Immune checkpoint inhibitors to treat cutaneous malignancies","volume":"83","author":"Barrios","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1177\/1758834014566428","article-title":"Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma","volume":"7","author":"Welsh","year":"2015","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1111\/exd.14144","article-title":"Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?","volume":"29","year":"2020","journal-title":"Exp. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.jid.2017.10.025","article-title":"Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions","volume":"138","author":"Slominski","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12728","DOI":"10.1111\/jpi.12728","article-title":"Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells","volume":"70","author":"Bilska","year":"2021","journal-title":"J. Pineal Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, H.S., Kim, T.-J., and 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.","DOI":"10.1371\/journal.pone.0092627"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"194","DOI":"10.32794\/mr11250057","article-title":"Melatonin inhibits human melanoma cells proliferation and invasion via cell cycle arrest and cytoskeleton remodeling","volume":"3","author":"Moreno","year":"2020","journal-title":"Melatonin Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/s41598-017-01305-2","article-title":"Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways","volume":"7","author":"Janjetovic","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/jpi.12018","article-title":"Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2\u2019-deoxyguanosine) in ex vivo human skin","volume":"54","author":"Fischer","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e12610","DOI":"10.1111\/jpi.12610","article-title":"Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT-1 melanoma cells","volume":"67","author":"Kim","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/jpi.12264","article-title":"Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis","volume":"59","author":"Reiter","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/s12935-021-01892-1","article-title":"An updated review of mechanistic potentials of melatonin against cancer: Pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress","volume":"21","author":"Mehrzadi","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2014.07.024","article-title":"Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro","volume":"404","author":"Kim","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Alvarez-Artime, A., Cernuda-Cernuda, R., Naveda, F.A., Cepas, V., Gonzalez-Menendez, P., Fernadez-Vega, S., Quiros-Gonzalez, I., Sainz, R.M., and Mayo, J.C. (2020). Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020548"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/cbin.10030","article-title":"Pharmacological doses of melatonin induce alterations in mitochondrial mass and potential, bcl-2 levels and K+ currents in UVB-exposed U937 cells","volume":"37","author":"Canonico","year":"2012","journal-title":"Cell Biol. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.18632\/oncotarget.6407","article-title":"Melatonin inhibits AP-2\u03b2\/hTERT, NF-\u03baB\/COX-2 and Akt\/ERK and activates caspase\/Cyto C signaling to enhance the antitumor activity of berberine in lung cancer cells","volume":"7","author":"Lu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e12557","DOI":"10.1111\/jpi.12557","article-title":"Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types","volume":"66","author":"Lv","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.jphotobiol.2015.10.006","article-title":"Melatonin as a possible antidote to UV radiation induced cutaneous damages and im-mune-suppression: An overview","volume":"153","author":"Goswami","year":"2015","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jdermsci.2016.08.007","article-title":"Dose dependent sun protective effect of topical melatonin: A randomized, placebo-controlled, double-blind study","volume":"84","author":"Scheuer","year":"2016","journal-title":"J. Dermatol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"68338","DOI":"10.18632\/oncotarget.20124","article-title":"Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells","volume":"8","author":"Gatti","year":"2017","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"436","DOI":"10.32794\/mr11250071","article-title":"Melatonin inhibits growth of B16 melanoma in C57BL\/6 mice","volume":"3","author":"Agil","year":"2020","journal-title":"Melatonin Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Thyagarajan, A., Kadam, S.M., Liu, L., Kelly, L.E., Rapp, C.M., Chen, Y., and Sahu, R.P. (2018). Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010032"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.2174\/1389557519666190327163644","article-title":"Exploring Signaling Pathways and Pancreatic Cancer Treatment Approaches Using Genetic Models","volume":"19","author":"Khader","year":"2019","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Thyagarajan, A., Alshehri, M.S.A., Miller, K.L., Sherwin, C.M., Travers, J.B., and Sahu, R.P. (2019). Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches. Cancers, 11.","DOI":"10.3390\/cancers11111627"}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/11\/1\/9\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:06:01Z","timestamp":1760119561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/11\/1\/9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,14]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["medsci11010009"],"URL":"https:\/\/doi.org\/10.3390\/medsci11010009","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,14]]}}}