期刊
CANCER MANAGEMENT AND RESEARCH
卷 10, 期 -, 页码 1231-1241出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/CMAR.S156530
关键词
DCA; autophagy; multi-drug resistance; non-small-cell lung cancer; paclitaxel; xenograft nude mice; chemosensitization
类别
资金
- National Natural Science Foundation of China [81702247, 81472188]
- Basic Science and Frontier Technology Project of Chongqing [cstc2017jcyjAX0048]
- Clinical Research Project of Xinqiao Hospital [2015YLC21]
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.
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