Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan ; Petra University Pharmaceutical Center, University of Petra, Amman, Jordan.
Petra University Pharmaceutical Center, University of Petra, Amman, Jordan.
Onco Targets Ther. 2014 Feb 7;7:193-201. doi: 10.2147/OTT.S56688. eCollection 2014.
Dichloroacetate (DCA) is one of the new, promising anticancer drugs. DCA restores normal mitochondrial function and enables cancer cells to undergo apoptosis. In addition, DCA was found to modulate certain signaling pathways involving some transcription factors. The latter encouraged us to study DCA immunomodulatory activity on cytokines and their association with increasing DCA cancer cell cytotoxicity.
Cell viability assay was used to determine the effect of different concentrations of DCA on the survival of 3-methylcholanthrene (MCA) fibrosarcoma cell line. DCA decreased the percent survival of MCA fibrosarcoma in a dose-dependent manner (P<0.01). Furthermore, this percent survival was further reduced when MCA fibrosarcoma cells were cocultured with mouse splenocytes. The latter was observed at 10 mM DCA (P<0.01), and the inhibitory concentration at 50% dropped from 23 mM to 15.6 mM DCA (P<0.05). In addition, DCA significantly enhanced interferon (IFN)-γ but not interleukin (IL)-17 production levels in unstimulated and stimulated mouse spleen cells. To investigate the mechanism of DCA on IFN-γ production, DCA cytokine modulatory effect was tested on unstimulated macrophages, T-cells, and natural killer cells. DCA significantly increased IL-12 production from macrophages but did not modulate the production of IFN-γ from either T-cells or natural killer cells. Moreover, the DCA-enhancing effect on IFN-γ production was reversed by anti-IL-12 antibody. Also, the DCA cytokine modulatory effect was tested in vivo after inducing mouse skin inflammation using phorbol 12-myristate 13-acetate (PMA). DCA restored PMA-lowered IFN-γ and IL-12 levels and normalized PMA-increased transforming growth factor-β level, but it inhibited IL-10 levels even further (P<0.05).
DCA has immunomodulatory activity, mainly via activation of the IL-12-IFN-γ pathway and is able to modulate cytokines toward T helper 1 lymphocyte function. These DCA immunomodulatory effects are promising and further investigations are required to develop protocols for its use in cancer treatment.
二氯乙酸 (DCA) 是一种新的有前途的抗癌药物。DCA 恢复了正常的线粒体功能，使癌细胞能够凋亡。此外，还发现 DCA 调节了某些涉及某些转录因子的信号通路。这促使我们研究 DCA 对细胞因子的免疫调节活性及其与增加 DCA 癌细胞细胞毒性的关系。
细胞活力测定用于确定不同浓度的 DCA 对 3-甲基胆蒽（MCA）纤维肉瘤细胞系存活的影响。DCA 以剂量依赖性方式降低 MCA 纤维肉瘤的存活率（P<0.01）。此外，当 MCA 纤维肉瘤细胞与小鼠脾细胞共培养时，这种存活率进一步降低。在 10 mM DCA 时观察到这种情况（P<0.01），抑制浓度从 23 mM 下降到 15.6 mM DCA（P<0.05）。此外，DCA 显著增强了未刺激和刺激的小鼠脾细胞中干扰素 (IFN)-γ 但不是白细胞介素 (IL)-17 的产生水平。为了研究 DCA 对 IFN-γ 产生的机制，测试了 DCA 对未刺激的巨噬细胞、T 细胞和自然杀伤细胞的细胞因子调节作用。DCA 显著增加了巨噬细胞中 IL-12 的产生，但未调节 T 细胞或自然杀伤细胞中 IFN-γ 的产生。此外，抗 IL-12 抗体逆转了 DCA 对 IFN-γ 产生的增强作用。此外，在使用佛波醇 12-肉豆蔻酸 13-乙酸酯 (PMA) 诱导小鼠皮肤炎症后，在体内测试了 DCA 细胞因子调节作用。DCA 恢复了 PMA 降低的 IFN-γ 和 IL-12 水平，并使 PMA 增加的转化生长因子-β水平正常化，但进一步抑制了 IL-10 水平（P<0.05）。
DCA 具有免疫调节活性，主要通过激活 IL-12-IFN-γ 途径，并能够调节细胞因子向辅助性 T 淋巴细胞功能。这些 DCA 免疫调节作用很有前途，需要进一步研究以制定其在癌症治疗中的应用方案。
