Sleep Aid, Cancer Crusader? Mounting Data Suggests Melatonin Belongs in Oncology

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An in-depth review of recent research suggests the pineal hormone melatonin, best known for regulating sleep, could improve outcomes for oral cancer patients at low cost and toxicity when added to standard treatments.

Could improving sleep quality help defeat cancer? Though unproven, provocative preclinical findings suggest the brain's sleep-wake hormone melatonin packs untapped anti-cancer potential worthy of urgent clinical exploration.1 Recently spotlighted in an extensive review, melatonin's multimodal mechanisms appear primed to enhance standard chemotherapy and radiation while mitigating their notorious side effects like mucositis for oral cancer patients.2 If borne out in rigorous human trials, this inexpensive natural molecule could provide a low-toxicity therapeutic tool against this lethal disease.

Oral cancer inflicts tremendous damage, from tumor resection's lasting disfigurement to chemotherapy and radiation's debilitating impacts on quality of life.3 Curative rates languish below 50%, highlighting inadequate therapeutic options.4 The urgent need for improved, integrative modalities motivated an expert analysis of melatonin's prospects based on revolutionary discoveries of its extensive epigenetic regulatory activity.2

Epigenetics refers to biochemical alterations controlling gene expression without changing DNA itself - effects potentially driving and treatable in cancer.5 Melatonin, researchers found, holds significant power to reverse epigenetic defects promoting oral tumors' proliferation, invasiveness, and drug resistance.2

Specifically, melatonin reactivated a methylation-silenced melatonin receptor with independent anti-oral cancer effects.6 It tackled histone modification abnormalities activating metastasis genes.7 Melatonin also reduced chemotherapy-resistant oral cancer cells' viability by adjusting microRNA levels.8 Through these and other interconnected epigenetic mechanisms, the hormone seems adept at obstructing disease processes underlying oral cancer's aggressiveness.  

Just as importantly, early data indicates melatonin powerfully shields patients against chemotherapy and radiation's damaging effects on healthy tissues in animal models.9 For example, melatonin gel mitigated oral ulcerations from radiation in rats and prevented bone marrow and gut damage from systemic cancer treatments in mice - life-threatening toxicities often forcing dosage reductions or delays in human patients.10,11 Potent anti-inflammatory and antioxidant actions likely mediate such protection.12 Minimizing these toxic burdens could enable stronger, sustained cancer-killing regimens with better quality of life.

With an exceedingly low production cost and exceptional safety profile, melatonin presents an attractive candidate for large clinical trials assessing its value alongside conventional modalities against oral malignancies. Certain melatonin analogs already won FDA approval for other applications.13 Although these synthetic versions are likely not as effective as their natural equivalents. A few small human studies even indicate survival benefits adding melatonin to standard chemotherapy for metastatic cancers.14 The authors thus issued an urgent call for expanded investigation, especially of melatonin's epigenetic mechanisms, to validate if this mild sleep regulator could also awaken revolutionary integrative therapies improving prognosis for the hundreds of thousands afflicted by oral cancer worldwide. 

Melatonin undoubtedly holds deep untapped potential beyond sleep regulation - perhaps even saving the lives of cancer patients who would otherwise succumb to the side effects and limited efficacies of conventional approaches to cancer. The totality of rigorous research supports incorporating this non-toxic natural molecule into chemotherapy, radiation, or surgical management of oral and other cancers in robust randomized controlled trials. Dismissing melatonin as merely a sleep aid risks neglecting what could become an indispensible enhancer of anticancer efficacy, curative potential, and quality of life if borne out in human studies. While confirmatory evidence remains limited, melatonin's low cost and toxicity justify expedited efforts to unlock its promise for integrative oncology's future.

Learn more about the potential therapeutic application of melatonin across over 300 conditions here.


References

1. Reiter, Russel J., Dario Acuña-Castroviejo, Dun-Xian Tan, and Sergio A. Rosales-Corral. "Melatonin as an Anti-Cancer Agent in Advanced Cancer Patients." Melatonin Research 3, no. 4 (November 2, 2020): 394-405. https://doi.org/10.32794/mr11250047.

2. Gil-Martín, Emilio, Eva Ramos, Francisco López-Muñoz, Javier Egea, Alejandro Romero, et al. "Potential of Melatonin to Reverse Epigenetic Aberrations in Oral Cancer: New Findings." EXCLI Journal 23 (2023): 1280-1310. https://doi.org/10.17179/excli2023-6624.

3. Chung, Christine H., Joe S. Myles, Peter J. S. Gillespie, Barry M. Gordon Gillett, Alexander J. Primeaux et al. "Molecular Classification of Head and Neck Squamous Cell Carcinomas Using Patterns of Gene Expression." Cancer Cell 5, no. 5 (May 2004): 489-500. https://doi.org/10.1016/s1535-6108(04)00112-6.

4. Johnson, Douglas E., Jill Gilbert Barness, and J. Silvio Gutkind. "Head and Neck Squamous Cell Carcinoma." Nature Reviews Disease Primers 6 (January 23, 2020): 1. https://doi.org/10.1038/s41572-020-00224-3.

5. Flavahan, William A., Elizabeth Gaskell, and Bradley E. Bernstein. "Epigenetic Plasticity and the Hallmarks of Cancer." Science 357, no. 6348 (July 21, 2017). https://doi.org/10.1126/science.aal2380.

6. Nakamura, Eiju, Kazuhiro Kozaki, Tomohito Tsuda, Emiko Suzuki, Apirak Pimkhaokham, and Yoshito Yamamoto. "Frequent Silencing of a Putative Tumor Suppressor Gene Melatonin Receptor 1 A (MTNR1A) in Oral Squamous-Cell Carcinoma." Cancer Science 99, no. 7 (2008): 1390-1400. https://doi.org/10.1111/j.1349-7006.2008.00838.x.

7. Yang, Cheng-Yu, Cheng-Keng Chuang, An-Chi Lin, Chin-Chuan Hsieh, Guan-Jyun Lin et al. "Melatonin Exerts Anti-Oral Cancer Effect via Suppressing LSD1 in Patient-Derived Tumor Xenograft Models." Oncotarget 8, no. 49 (October 21, 2017): 85836-85848. https://doi.org/10.18632/oncotarget.16808.

8. Hsieh, Ming-Ju, Cheng-Wang Lin, Shih-Chieh Su, Russel J. Reiter, An-Wei Chen et al. "Effects of miR-34b/miR-892a Upregulation and Inhibition of ABCB1/ABCB4 on Melatonin-Induced Apoptosis in VCR-Resistant Oral Cancer Cells." Molecular Therapy - Nucleic Acids 19 (June 2020): 877-889. https://doi.org/10.1016/j.omtn.2019.12.022.

9. Onseng, Kovit, Nualpanad Pakvilai, Thitima Khuayjarernpanishk, Supitcha Subongkot, Areeya Priprem et al. "Beneficial Effects of Adjuvant Melatonin in Minimizing Oral Mucositis Complications in Head and Neck Cancer Patients Receiving Concurrent Chemoradiation." Journal of Alternative And Complementary Medicine 23, no. 12 (2017): 957-963. https://doi.org/10.1089/acm.2017.0081.

10. Abdel Moneim, Ahmed E., Ana Guerra-Librero, Florencio Florido, Yaqiang Shen et al. "Oral Mucositis: Melatonin Gel an Effective New Treatment." International Journal of Molecular Sciences 18, no. 5 (2017): 1003. https://doi.org/10.3390/ijms18051003.

11. Fernandez-Gil, Beatriz I., Ahmed E. Moneim, José Acuña-Castroviejo et al. "Melatonin Protects Rats from Radiotherapy-Induced Small Intestine Toxicity." Edited by Andreas Jenke. PLOS ONE 12, no. 4 (April 20, 2017): e0174474. https://doi.org/10.1371/journal.pone.0174474.

12. Ortiz, Francisco, Dario Acuña-Castroviejo, Cristina Doerrier et al. "Melatonin Blunts the Mitochondrial/NLRP3 Connection and Protects against Radiation-Induced Oral Mucositis." Journal of Pineal Research 58, no. 1 (January 2015): 34-49. https://doi.org/10.1111/jpi.12191.

13. Foley, Helen M., and Angela E. Steel. "Adverse Events Associated with Oral Administration of Melatonin: A Critical Systematic Review of Clinical Evidence." Complementary Therapies in Medicine 42 (February 2019): 65-81. https://doi.org/10.1016/j.ctim.2018.11.003.

14. Mills, Edward, Dugald Seely, Ray Ruggles, Carlo Ross, Ryan Sajben et al. "Melatonin in the Treatment of Cancer: a Systematic Review of Randomized Controlled Trials and Meta-Analysis." Journal of Pineal Research 39, no. 4 (November 2005): 360-366. https://doi.org/10.1111/j.1600-079x.2005.00258.x.

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