Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.
Chloroquine potentiates the anticancer effect of sunitinib on renal cell carcinoma by inhibiting autophagy and inducing apoptosis.
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氯喹通过抑制自噬和诱导凋亡来增强舒尼替尼对肾细胞癌的抗癌作用。
DOI：
10.3892/ol.2017.7635
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发表时间：
2018-03
期刊：
影响因子：
2.9
通讯作者：
Zhao YL
中科院分区：
文献类型：
--
作者：
Li ML;Xu YZ;Lu WJ;Li YH;Tan SS;Lin HJ;Wu TM;Li Y;Wang SY;Zhao YL
以舒尼替尼为基础的辅助化疗联合氯喹（CQ）治疗肾细胞癌（RCC）正在进行临床试验；但其抗RCC作用及机制尚不清楚。本研究探讨了舒尼替尼联合 CQ 的抗肾细胞癌作用及其潜在机制。 MTT 分析表明，CQ 增强了舒尼替尼对 OS-RC-2 RCC 细胞系的增殖抑制作用。 CQ 抑制 OS-RC-2 中舒尼替尼诱导的自噬，这通过舒尼替尼诱导的自噬空泡、酸性囊泡细胞器形成、轻链 3 (LC3)-II 招募至自噬体以及 LC3-I 向 LC3-II 的转化受到抑制来证明。 CQ 对自噬的抑制增强了舒尼替尼诱导的细胞凋亡，其特征是 caspase-3、caspase-9、Bcl-2 和 p53 的激活。此外，将 OS-RC-2 细胞暴露于 CQ 和舒尼替尼会导致 AKT、结节性硬化症复合物 2、雷帕霉素的机制靶标和 p70 核糖体 S6 激酶受到抑制，这些都与细胞增殖相关。在体内研究中，与单独使用舒尼替尼组相比，在小鼠中，舒尼替尼与 CQ 的组合显着降低了 OS-RC-2 细胞异种移植物的生长。总之，本研究证明CQ可能通过抑制舒尼替尼诱导的自噬增强舒尼替尼的抗RCC作用，并提高细胞凋亡率。抑制细胞增殖也可能在舒尼替尼和 CQ 的协同抗肿瘤作用中发挥作用。这些数据表明，舒尼替尼与 CQ 的联合治疗可能是 RCC 辅助化疗的一种有前景的策略。
Sunitinib based adjuvant chemotherapy combined with chloroquine (CQ) for the treatment of renal cell carcinoma (RCC) is in clinical trials; however, its anti-RCC effect and the mechanism remain unclear. In the present study, the anti-RCC effect of sunitinib with CQ and the underlying mechanism was investigated. An MTT assay demonstrated that CQ enhanced the proliferation inhibitory effect of sunitinib against the OS-RC-2 RCC cell line. CQ inhibited sunitinib-induced autophagy in OS-RC-2, which was evidenced by the inhibition of autophagic vacuoles, acidic vesicular organelle formation, light chain 3 (LC3)-II recruitment to the autophagosomes and the conversion of LC3-I to LC3-II, as induced by sunitinib. The inhibition of autophagy by CQ enhanced sunitinib-induced apoptosis, which was characterized by the activation of caspase-3, caspase-9, Bcl-2 and p53. Additionally, the exposure of OS-RC-2 cells to CQ and sunitinib resulted in the inhibition of AKT, tuberous sclerosis complex 2, mechanistic target of rapamycin and p70 ribosomal S6 kinase, which are associated with cell proliferation. In in vivo study, a combination of sunitinib with CQ in mice significantly reduced OS-RC-2 cell xenograft growth compared with the sunitinib alone group. In conclusion, the present study demonstrated that CQ may enhance the anti-RCC effect of sunitinib by inhibiting the autophagy induced by sunitinib, and enhance the rate of apoptosis. Inhibiting cell proliferation may also serve a role in the synergistic antitumor effect of sunitinib and CQ. These data suggest that combination therapy of sunitinib with CQ may be a promising strategy for adjuvant chemotherapy in RCC.
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