Synergistic Effects of Melatonin on Radiosensitization in Carbon-ion Radiotherapy

• Published in: Anticancer research Vol. 44; no. 8; pp. 3295 - 3306
• Main Authors: Ju, Mengyang, Minami, Kazumasa, Katsuki, Shohei, Takenaka, Wataru, Tatekawa, Shotaro, Tamari, Keisuke, Koizumi, Masahiko, Takahashi, Yutaka, Ogawa, Kazuhiko
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.08.2024
• Subjects: Animals; Antitumor activity; Bioinformatics; Carbon; Carbon cycle; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Cell Survival - radiation effects; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; DNA damage; DNA repair; DNA Repair - drug effects; DNA Repair - radiation effects; DNA sequencing; Double-strand break repair; Gene sequencing; Genes; Heavy Ion Radiotherapy; Humans; Ion irradiation; Irradiation; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Melanoma, Experimental - radiotherapy; Melatonin; Melatonin - pharmacology; Metastases; Mice; Osteosarcoma; Photons; Radiation damage; Radiation therapy; Radiation tolerance; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Radiosensitivity; Radiosensitization; Ribonucleic acid; RNA; Survival; Synergistic effect; radiosensitivity; G2/M checkpoint; Carbon-ion radiotherapy; melanoma; gene set enrichment analysis; melatonin; DNA double-strand break; osteosarcoma
• ISSN: 0250-7005; 1791-7530; 1791-7530
• DOI: 10.21873/anticanres.17148

Despite the established antitumor effectiveness and synergistic interactions of melatonin with photon irradiation, its role in carbon-ion radiotherapy remains uncertain. This study aimed to elucidate the mechanisms and potential clinical advantages of combining exogenous melatonin therapy with carbon-ion radiotherapy. The investigation assessed the impact of combining exogenous melatonin with photon or carbon-ion irradiation on cell-cycle modulation and DNA-repair capability using the melanoma cell line B16F10. RNA sequencing and bioinformatics analysis were conducted to explore mechanisms and evaluate potential clinical benefits, with validation performed on the osteosarcoma cell line LM8. Pre-treatment with melatonin reduced the survival fraction of B16F10 and LM8 cells upon exposure to photon and carbon-ion radiation. Mechanistically, melatonin was found to inhibit G /M arrest, preserve DNA damage, and suppress key genes involved in DNA double-strand break repair after 8 Gy carbon-ion radiation. Furthermore, RNA sequencing and bioinformatics analysis revealed favorable changes in genes associated with survival and metastasis, highlighting potential clinical significance. LM8 cells treated with melatonin exhibited increased radiosensitivity and suppression of DNA-repair proteins. The combination of exogenous melatonin not only heightened radiosensitivity and modulated hallmark tumor gene sets in vitro but also markedly suppressed the efficiency of DNA double-strand break-repair pathway, thus enhancing the cytotoxicity of carbon-ion radiotherapy.