Dichloroacetate modulates cytokines toward T helper 1 function via induction of the interleukin-12–interferon-γ pathway
Mujtaba M Badr,1,2 Nidal A Qinna,1,2 Fadi Qadan,2 Khalid Z Matalka1,2
1Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, 2Petra University Pharmaceutical Center, University of Petra, Amman, Jordan
Background: 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.
Methods and results: 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-ß level, but it inhibited IL-10 levels even further (P<0.05).
Conclusion: 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.
Keywords: dichloroacetate, fibrosarcoma, cytokines, IL-12, IFN-γ, inflammation