Melatonin synergizes BRAF‐targeting agent dabrafenib for the treatment of anaplastic thyroid cancer by inhibiting AKT/hTERT signalling

• Published in: Journal of cellular and molecular medicine 2020-10, Vol.24 (20), p.12119-12130
• Main Authors: Liao, Yina, Gao, Yao, Chang, An, Li, Zongjuan, Wang, Huayu, Cao, Jing, Gu, Wei, Tang, Ranran
• Format: Article
• Language: English
• Subjects: AKT protein; AKT/hTERT; anaplastic thyroid cancer; Antibodies; Apoptosis; Apoptosis - drug effects; Cancer therapies; Caspases - metabolism; Cell adhesion & migration; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell viability; dabrafenib; Down-Regulation - drug effects; Drug development; Drug dosages; Drug Synergism; Enzyme inhibitors; Gene expression; Humans; Imidazoles - therapeutic use; Kinases; Melatonin; Melatonin - pharmacology; Melatonin - therapeutic use; Models, Biological; Mutation; Neoplasm Invasiveness; Original; Oximes - therapeutic use; Proteins; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Telomerase - metabolism; Telomerase reverse transcriptase; Thyroid cancer; Thyroid Carcinoma, Anaplastic - drug therapy; Thyroid Neoplasms - drug therapy; Tumors
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15854

As a selective inhibitor of BRAF kinase, dabrafenib has shown potent anti‐tumour activities in patients with BRAFV600E mutant anaplastic thyroid cancer. However, the resistance of thyroid cancer cells to dabrafenib limited its therapeutic effect. The effects of melatonin and dabrafenib as monotherapy or in combination on the proliferation, cell cycle arrest, apoptosis, migration and invasion of anaplastic thyroid cancer cells were examined. The molecular mechanism involved in drug combinations was also revealed. Melatonin enhanced dabrafenib‐mediated inhibition of cell proliferation, migration and invasion, and promoted dabrafenib‐induced apoptosis and cell cycle arrest in anaplastic thyroid cancer cells. Molecular mechanistic studies further uncovered that melatonin synergized with dabrafenib to inhibit AKT and EMT signalling pathways. Furthermore, melatonin and dabrafenib synergistically inhibited the expression of hTERT, and the inhibition of cell viability and the induction of cell cycle arrest mediated by the combination of these two drugs were reversed by hTERT overexpression. Taken together, our results demonstrated that melatonin synergized the anti‐tumour effect of dabrafenib in human anaplastic thyroid cancer cells by inhibiting multiple signalling pathways, and provided new insights in exploring the potential therapeutic targets for the treatment of anaplastic thyroid cancer.