Abstract
IntroductionDichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The pro-apoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis.MethodsIn the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water.ResultsMice treated with DCA displayed much slower onset of CIA and significantly lower severity (P < 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell- or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group).ConclusionOur results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.
Highlights
Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders
The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls
Several lines of evidence show that the female hormone estrogen affects both the incidence and the progression of Rheumatoid arthritis (RA) in BMD: bone mineral density; collagen type II (CII): collagen II; CIA: collagen II-induced arthritis; DCA: dichloroacetate; DTH: delayed-type hypersensitivity; IL: interleukin; OVX: ovariectomy; OXA: oxazolone; pQCT: peripheral quantitative computed tomography; RA: rheumatoid arthritis; TNF: tumor necrosis factor
Summary
Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. DCA was found to act as an efficient tumor growth inhibitor, both in vitro and in vivo, by shifting glucose metabolism from glycolysis to glucose oxidation in malignant cells. This shifting results in the release of pro-apoptotic mediators and decreases proliferation in malignant cells, eliminating active tumor cells while leaving the normal cells unaffected [1]. Several lines of evidence show that the female hormone estrogen affects both the incidence and the progression of RA in BMD: bone mineral density; CII: collagen II; CIA: collagen II-induced arthritis; DCA: dichloroacetate; DTH: delayed-type hypersensitivity; IL: interleukin; OVX: ovariectomy; OXA: oxazolone; pQCT: peripheral quantitative computed tomography; RA: rheumatoid arthritis; TNF: tumor necrosis factor
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