Shanghai Center for Thyroid Disease, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, China.
J Cell Mol Med. 2020 Oct;24(20):12119-12130. doi: 10.1111/jcmm.15854. Epub 2020 Sep 15.
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.
达布拉非尼作为 BRAF 激酶的选择性抑制剂，在 BRAFV600E 突变型间变性甲状腺癌患者中显示出强大的抗肿瘤活性。然而，甲状腺癌细胞对达布拉非尼的耐药性限制了其治疗效果。本研究旨在探讨褪黑素和达布拉非尼单药或联合用药对间变性甲状腺癌细胞增殖、细胞周期阻滞、凋亡、迁移和侵袭的影响，并揭示药物联合作用的分子机制。褪黑素增强了达布拉非尼对间变性甲状腺癌细胞增殖、迁移和侵袭的抑制作用，并促进了达布拉非尼诱导的细胞凋亡和细胞周期阻滞。分子机制研究进一步揭示，褪黑素与达布拉非尼协同抑制 AKT 和 EMT 信号通路。此外，褪黑素和达布拉非尼协同抑制端粒酶反转录酶（hTERT）的表达，而过表达 hTERT 可逆转这两种药物联合抑制细胞活力和诱导细胞周期阻滞的作用。综上所述，本研究结果表明，褪黑素通过抑制多条信号通路增强了达布拉非尼在人源性间变性甲状腺癌细胞中的抗肿瘤作用，为探索治疗间变性甲状腺癌的潜在治疗靶点提供了新的思路。
