Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics
Abstract
:1. Introduction
2. Epidemiology of Oral Cancer
3. The Role of Melatonin in the Oral Cavity: Functionality and Alterations in Oral Cancer
4. Responses Mediated by Melatonin Receptors in Oral Cancer
5. Melatonin in Combination with Conventional Treatment for Oral Cancer and Safety Profile
6. Epigenetic Regulation of Melatonin in Oral Cancer
6.1. Epigenetic Methylation of DNA
6.2. Epigenetic Modification of Chromatin Structure
6.3. Non-Coding micro-RNAs
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Model | Melatonin Combined with Other Drugs | Effect | Reference | |
---|---|---|---|---|
Cal 27 and SCC-9 human squamous cell carcinoma lines | MLT (0.1, 0.5 or 1 mM) plus rapamycin (20 nM) | Enhanced cytotoxic effects of rapamycin in HNSCC cells | [16] | |
In vitro studies | Cal 27 and SCC-9 human squamous cell carcinoma lines | MLT (0.1, 0.5, 1 and 5 mM) combined with 8 Gy irradiation and 10 µM Cisplatin | Improved effectiveness of chemo- and radiotherapy | [17] |
OSCC cells | MLT (0,5 and 5 mM) combined with 5-FU (1 and 10 µM) | Potentiated cytotoxicity of 5-FU | [57] | |
Male Wistar rats | 7.5 Gy to oral mucosa for 5 days plus 3% MLT gel for 21 days post-irradiation | Inhibited radiotherapy-induced mucositis | [53] | |
In vivo studies | OSCC-xenografted mice | MLT (20 mg/kg/day) combined with 5-FU (20 mg/kg, twice per week) for 4 weeks | Inhibited OSCC tumor growth | [57] |
Cal 27 cells -xenografted rats | Rapamycin (1 mg/kg i.p.) for 10 days plus injection of MLT (300 mg/kg s.c.) 1 day before each rapamycin administration | Ameliorated the toxicity of rapamycin in normal cells | [16] | |
Clinical trial in 27 patients with metastatic solid tumor in HNC | MLT (20 mg/day orally every day) combined with 5-FU and Cisplatin | Increased 1-year survival and tumor regression rate; and side effects reduced | [56] | |
Human studies | Clinical trial in 39 patients with HNC under concurrent chemoradiation | MLT gargle (20 mg) before irradiation, and MLT capsules (20 mg) taken before bedtime during 7 weeks of concurrent chemoradiation | Delayed onset of oral mucositis and reduced amount of morphine required to alleviate the pain vs controls | [58] |
Oncologic Treatment | Pathological Complication | Melatonin Treatment | Clinical Observations | References |
---|---|---|---|---|
Concurrent chemoradiation (5 days/week of radiation for 7 weeks; total dose ≥50 Gy), plus cisplatin chemotherapy | Oral mucositis | Oral gargle (20 mg/10 mL or 20 mg oral dose) | Adjuvant MLT delayed the onset of oral mucositis, reducing the palliative morphine required to control pain. | [58] |
Male Wistar rats irradiated under anesthesia with a dose of 7.5 Gy/day for 5 days | Oral mucositis | 45 mg/day for 21 days postirradiation, either by local mouth application (MLT gel; 48 h before each irradiation, 3 times/day) or by s.c. injection each day | MLT prevented mucosal disruption and ulcer formation by blunting inflammasome signaling activation in the tongue | [53] |
Epigenetic Control | Experimental Model | Melatonin Treatment | Main Findings | References |
---|---|---|---|---|
DNA methylation | OSCC cell lines | The loss by homozygous deletion or silencing by CpG hypermethylation of the MLT receptor 1A (MTNR1A) gene was associated with cancer status and tumor phenotype | [50] | |
Histone modification | Patient-derived tumor xenografts models overexpressing LSD1. Mouse-based subcutaneous OC SCC25-xenograft model. OSCC cell lines. | 20 mg/kg daily, i.p., for 24 and 42 days. 0–20 mM for 24 h 2–4 mM for 24 and 48 h | MLT demonstrated anti-OC activity through LSD1 down-regulation | [87] |
HSC-3 and OECM-1 OC cell lines | 1 mM for 24 h | MLT inhibited migration of tumor cells through down-regulation of MMP-9 expression and activity by decreasing CREBBP/EP300-dependent H3 and H4 histone acetylation on MMP-9 promoter | [90] | |
Promoter activity | HONE-1, NPC-39 and NPC-BM nasopharyngeal carcinoma cell lines. | 0.5–1 mM | MLT reduced MMP-9 promoter activity through inhibition of SP-1 transcription factor expression | [91] |
SCC9, SCC25 and CAL27 OSCC cell lines. | 10 μg/mL for 72 h | MLT reduced miR-155 and increased miR-21. | [102] | |
Non-coding micro-RNAs | 121 OC specimens and 66 normal counterparts for the study of miR-24 expression HCT 116 and MCF-7 cells. | 1 μM for 72 h | MLT decreased miR-24 expression, which pairs with the regulation of cell proliferation, DNA damage and oncogenic transformation genes. | [100] |
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Capote-Moreno, A.; Ramos, E.; Egea, J.; López-Muñoz, F.; Gil-Martín, E.; Romero, A. Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics. Cancers 2019, 11, 1712. https://doi.org/10.3390/cancers11111712
Capote-Moreno A, Ramos E, Egea J, López-Muñoz F, Gil-Martín E, Romero A. Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics. Cancers. 2019; 11(11):1712. https://doi.org/10.3390/cancers11111712
Chicago/Turabian StyleCapote-Moreno, Ana, Eva Ramos, Javier Egea, Francisco López-Muñoz, Emilio Gil-Martín, and Alejandro Romero. 2019. "Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics" Cancers 11, no. 11: 1712. https://doi.org/10.3390/cancers11111712