Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer

被引:38
作者
Lu, Xiao [1 ]
Zhou, Dong [1 ]
Hou, Bing [1 ]
Liu, Quan-Xing [1 ]
Chen, Qian [2 ,3 ]
Deng, Xu-Feng [1 ,4 ]
Yu, Zu-Bin [1 ]
Dai, Ji-Gang [1 ]
Zheng, Hong [1 ]
机构
[1] Third Mil Med Univ, Xinqiao Hosp, Dept Thorac Surg, 183 Xinqiao St, Chongqing 400037, Peoples R China
[2] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing, Peoples R China
[3] Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China
[4] First Peoples Hosp Zunyi, Dept Cardiothorac Surg, Zunyi, Guizhou, Peoples R China
基金
中国国家自然科学基金;
关键词
DCA; autophagy; multi-drug resistance; non-small-cell lung cancer; paclitaxel; xenograft nude mice; chemosensitization; THERAPEUTIC TARGET; APOPTOSIS; HYDROXYCHLOROQUINE; CHLOROQUINE; TRIAL; MTOR; AMPK;
D O I
10.2147/CMAR.S156530
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Background: Chemotherapy is still the primary adjuvant strategy of cancer therapy; however, the emergence of multi-drug resistance has been a cause for concern. Autophagy has been demonstrated to have a protective role against chemotherapeutic drugs in cancer cells, and autophagy inhibition is generally considered to be a promising therapeutic strategy. However, the paucity of effective and specific autophagy inhibitors limits its application. Purpose: The objective of this study was to explore the effect of DCA, small molecular antitumor agent, on the autophagy regulation and chemosensitization in NSCLC cells. Methods: We investigated the autophagy regulation of dichloroacetate (DCA) by laser confocal microscopy and western blotting in A549 and H1975 cell lines. The MTT assay and flow cytometry was performed for explore the chemosensitization effectiveness of DCA. The results were verified with subcutaneous tumor model in nude mice and the immunohistochemistry was applied for assessing the level of cell apoptosis and autophagy in vivo post treatment. Results: We found that DCA, which exhibited antitumor properties in various carcinoma models, induced apoptosis of non-small cell lung cancer cells (NSCLC) by inhibiting cancer cell autophagy. Furthermore, Perifosine, an AKT inhibitor, can greatly weaken the capacity of inducing apoptosis by DCA. The results indicate that the AKT-mTOR pathway, a main negative regulator of autophagy, is involved in the DCA-induced inhibition of autophagy. Then, we detected the effectiveness of autophagy inhibition by DCA. When used in co-treatment with the chemotherapeutic drug paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited proliferation in A549 and H1975 cells. The results of the xenograft experiment demonstrate that co-treatment of PTX and DCA can significantly decrease cell proliferation in vivo and prolong the survival of mice. Conclusion: Our results suggest that DCA can inhibit cell autophagy induced by chemotherapeutics, providing a new avenue for cancer chemotherapy sensitization.
引用
收藏
页码:1231 / 1241
页数:11
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