Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310021, P.R. China.
Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310021, P.R. China.
Oncol Rep. 2018 Feb;39(2):711-720. doi: 10.3892/or.2017.6118. Epub 2017 Nov 28.
The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.
多靶点激酶抑制剂索拉非尼已被批准用于治疗晚期分化型甲状腺癌患者。然而，不同患者对索拉非尼的敏感性不同，长期接受索拉非尼治疗的患者获益有限。在索拉非尼获得耐药后，继续治疗对大多数患者无益。自噬可在多种癌症治疗中被诱导，并在癌症治疗中发挥重要作用。自噬在索拉非尼治疗甲状腺癌中的作用尚未得到充分证实。本研究旨在探讨索拉非尼治疗甲状腺癌时是否能诱导自噬，并探讨其潜在的作用机制，以及探索增强索拉非尼治疗敏感性的潜在策略。氯喹（CQ）是一种自噬抑制剂，已被报道能提高多种癌症治疗的敏感性。我们采用索拉非尼、CQ 或索拉非尼联合 CQ 处理甲状腺癌异种移植模型鼠，观察到 CQ 或索拉非尼治疗均能抑制肿瘤生长，而联合使用索拉非尼和 CQ 的小鼠肿瘤生长明显较单独使用索拉非尼或 CQ 的小鼠减少。Western blot 结果表明，索拉非尼能同时抑制甲状腺癌细胞中 MAPK 和 AKT/mTOR 通路的活性。索拉非尼能在体外和体内诱导甲状腺癌细胞发生自噬，这至少部分归因于 AKT/mTOR 通路的抑制。包括 CQ 在内的联合治疗能抑制索拉非尼诱导的自噬流。使用小干扰 RNA 沉默关键自噬基因 ATG5 也能增强索拉非尼的抗癌作用。总之，本研究揭示了抑制自噬能增强索拉非尼的抗癌作用，CQ 联合索拉非尼治疗可能是治疗晚期分化型甲状腺癌的一种潜在治疗策略。
