Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer
Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer
复制标题
抑制 AKT/mTOR 通路可增强索拉非尼对甲状腺癌的抗癌作用
DOI：
10.1089/cbr.2017.2187
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发表时间：
2017-06-01
影响因子：
3.4
通讯作者：
Li, Linfa
中科院分区：
文献类型：
--
作者：
Yi, Heqing;Ye, Xuemei;Li, Linfa
背景资料：索拉非尼是一种多激酶抑制剂，已被批准用于治疗晚期（131）碘（I-131）难治性分化型甲状腺癌（DTC）患者。然而，晚期I-131难治性DTC患者的无进展生存期较短，大多数DTC患者最终对索拉非尼产生耐药性。因此，需要开发新的治疗策略。材料与方法：在存在或不存在BEZ 235或针对AKT的小干扰RNA（siRNA）的情况下，用索拉非尼处理甲状腺癌细胞系8505 C和FTC 133。CCK 8试剂盒用于评估细胞活力。相关基因的蛋白质表达水平通过蛋白质印迹分析确定，而信使RNA表达水平通过实时PCR分析确定。进行流式细胞术以评估凋亡细胞的数量。结果：索拉非尼可同时抑制甲状腺癌细胞MAPK和PI 3 K/AKT/mTOR通路的活性。用NVP-BEZ 235、针对AKT的siRNA或索拉非尼处理8505 C和FTC 133细胞可诱导肿瘤细胞凋亡并导致肿瘤细胞增殖减少。索拉非尼联合NVP-BEZ 235或AKT siRNA抑制PI 3 K/AKT/mTOR增强了细胞凋亡和增殖抑制。结论：这项研究的证据表明，抑制MAPK和PI 3 K/AKT/mTOR途径的组合方法在甲状腺癌细胞系中发挥比单独索拉非尼更大的抗肿瘤作用。
Background: Sorafenib is a multikinase inhibitor that has been approved for the treatment of patients with advanced (131)iodine (I-131) refractory differentiated thyroid cancer (DTC). However, the progression-free survival of patients with advanced I-131 refractory DTC is short, and most DTC patients eventually acquire resistance to sorafenib. Therefore, new therapeutic strategies need to be developed. Materials and Methods: The thyroid cancer cell lines 8505C and FTC133 were treated with sorafenib in the presence or absence of BEZ235 or small interfering RNA (siRNA) directed against AKT. A CCK8 kit was used to evaluate cell viability. Protein expression levels of relevant genes were determined by Western blotting analysis, whereas messenger RNA expression levels were determined by real-time PCR analysis. Flow cytometry was performed to assess the number of apoptotic cells. Results: The results indicate that sorafenib simultaneously inhibited the activities of the MAPK and PI3K/AKT/mTOR pathways in thyroid cancer cells. Treatment of 8505C and FTC133 cells with NVP-BEZ235, siRNA against AKT, or sorafenib induced tumor cell apoptosis and led to reduced tumor cell proliferation. Sorafenib in combination with PI3K/AKT/mTOR inhibition by NVP-BEZ235 or AKT siRNA enhanced apoptosis and proliferation suppression. Conclusions: The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines.