Melatonin as a Radio-Sensitizer in Cancer
Abstract
:1. Introduction
2. Biological Effects of Radiation
3. Signaling Pathways of the Cellular Radiation Response
3.1. p53
3.2. DNA Double-Strand Break Repair Pathways
3.3. Apoptosis
3.4. Mitotic Catastrophe
3.5. Senescence
3.6. Autophagy
3.7. EGFR (Epidermal Growth Factor Receptor) Signalling
4. Radiosensitizers
5. Melatonin: An Antitumor Hormone
6. Radiosensitizing Effects of Melatonin on Cancer: Mechanisms Involved in the Radiosensitization Induced by Melatonin
6.1. Increase of Reactive Oxygen Species (ROS) Production
6.2. Modulation of Proteins Involved in Estrogen Biosynthesis
6.3. Impairment of Tumor Cells to DNA Repair
6.4. Modulation of Angiogenesis
6.5. Abolition of Inflammation
6.6. Induction of Apoptosis
6.7. Differentiation of Pre-Adipocytes
6.8. Modulation of Metabolism
7. Clinical Trials with Melatonin as an Adjuvant to Radiotherapy
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ROS | Reactive Oxigen Species |
HSP70 | Hear Shock Protein 70 |
p65 | Nuclear factor NF-kappa-B p65 subunit |
17β-HSD1 | 17β-Hidroxysteroid-dehydrogenase type 1 |
CDKN1 | cyclin-dependent kinase inhibitor 1 |
RAD50 | Double Strand Break Repair Protein |
DSB repair | Double Strand Break repair |
COX-2 | Ciclooxygenase-2 |
VEGF | Vascular endothelial growth factor |
ANG-2 | Angiopoietin-2 |
p-AKT | protein kinase B |
p-ERK | extracellular signal regulated kinase |
pNF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
IL-4 | Interleukine-4 |
p21 | cyclin-dependent kinase inhibitor 1 |
Bax | BCL2 Associated X, Apoptosis Regulator |
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Radiosensitizing Effects of Melatonin | Cell Type/In vivo Model | Reference | |
---|---|---|---|
Oxidative Stress | Increase ROS production | Head and neck squamous cell carcinoma | [52] |
Increase of HSP70 expression | Ovarian carcinoma cells | [53] | |
Activation of c-Jun NH2 kinase signaling | Human cervical cancer cells | [54] | |
Inhibition of p65 phosphorylation | Thyroid cancer cells | [55] | |
Modulation of estrogen biosynthesis | Decrease aromatase, sulfatase and 17β-HSD1 activity | Breast cancer cells | [56] |
Increase sulfotransferase activity | Breast cancer cells | [56] | |
Up-regulation of p53 protein | Breast cancer cells | [56,57,58] | |
Inhibition of cell proliferation, migration and tubular network | Endothelial cells | [59] | |
Decrease aromatase, sulfatase and 17β-HSD1 activity | Breast adipose fibroblasts | [60] | |
Inhibition of COX enzymes | Breast adipose fibroblasts | [60] | |
DNA repair mechanisms | Decrease the effectiveness of DNA repair proteins | Breast cancer cells | [61] |
Up-regulation of p53 protein | Breast cancer cells | [61,62,63] | |
Enhance DNA damage and reduce DNA repair mechanisms | Non-small-cell lung cancer cells Colorectal adenocarcinoma cells | [64] | |
Increase sensitivity to ionizing radiation | Colorectal carcinoma xenografts tumor model | [65] | |
Increase Cdkn1 and RAD50 proteins regulating DSB repair | Rat peripheral blood | [66] | |
Modulation of angiogenesis | Inhibition of pro-angiogenic factors (VEGF, ANG2) | Endothelial cells | [59] |
Decrease vascular area | Chick chorioallantoic membrane assay | [59] | |
Inhibition of the activation of p-AKT and p-ERK | Endothelial cells | [59] | |
Modulation of inflammatory response | Reduce DNA damage | Peripheral and Bone marrow lymphocytes | [67] |
Reduce the expression of inflammatory cytokines | Lung cancer cells | [68] | |
Reduce the expression of NF-kB, decreasing cytokines production | Lung cancer cells | [68,69] | |
Decrease IL-4 signaling pathways, reducing ROS production and inflammatory cells infiltration | Rats irradiated with 15Gy 60Co gamma rays | [69] | |
Induction of apoptosis | Enhance the apoptosis induced by laser irradiation | Ovarian cancer cells | [54] |
Upregulation of Akt and activation of Fas/FasL pathway | Malignant hematological cells | [70] | |
Upregulation of p53, p21 and Bax expression | Breast cancer cells | [71] | |
Inhibition of AkT and activation of pro-apoptotic caspases | Esophageal squamous cell carcinoma | [70] | |
Inhibition of COX-2 and stimulation of cell death receptors signaling pathways | Hepatocellular carcinoma | [72,73] | |
Modulation of metabolism | Inhibition of aerobic glycolysis and inhibition of metastasis | Leiomyosarcoma | [74] |
Inhibition of the Warburg effect | Ewing Sarcoma | [75] | |
Inhibition of aerobic glycolysis, lipid signaling and proliferative activity | Tissue-isolated breast cancer xenografts rats | [76] | |
Inhibition of aerobic glycolysis and proliferative activity | Tissue-isolated prostate cancer xenografts rats | [77] |
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Alonso-González, C.; González, A.; Menéndez-Menéndez, J.; Martínez-Campa, C.; Cos, S. Melatonin as a Radio-Sensitizer in Cancer. Biomedicines 2020, 8, 247. https://doi.org/10.3390/biomedicines8080247
Alonso-González C, González A, Menéndez-Menéndez J, Martínez-Campa C, Cos S. Melatonin as a Radio-Sensitizer in Cancer. Biomedicines. 2020; 8(8):247. https://doi.org/10.3390/biomedicines8080247
Chicago/Turabian StyleAlonso-González, Carolina, Alicia González, Javier Menéndez-Menéndez, Carlos Martínez-Campa, and Samuel Cos. 2020. "Melatonin as a Radio-Sensitizer in Cancer" Biomedicines 8, no. 8: 247. https://doi.org/10.3390/biomedicines8080247
APA StyleAlonso-González, C., González, A., Menéndez-Menéndez, J., Martínez-Campa, C., & Cos, S. (2020). Melatonin as a Radio-Sensitizer in Cancer. Biomedicines, 8(8), 247. https://doi.org/10.3390/biomedicines8080247