Dichloroacetate induces regulatory T-cell differentiation and suppresses Th17-cell differentiation by pyruvate dehydrogenase kinase-independent mechanism

Makita, Naoyuki; Ishiguro, Jun; Suzuki, Keisuke; Nara, Futoshi

doi:10.1111/jphp.12655

Cited by 12 publications

(13 citation statements)

References 27 publications

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“…Although most research points toward a negative role for glycolysis in Treg proliferation, it has become clear that complete depletion of glucose from cell culture medium is detrimental for in vitro Treg proliferation and suppressive function. Inhibition of glycolysis reduces intracellular pyruvate levels, thereby preventing the conversion to acetyl-CoA via PDHK for mitochondrial oxidative metabolism (Figure 2) and can consequently reduce Treg proliferation (77). Interestingly, glycolysis can potentially be modulated in a Treg-specific manner, as Treg convert glucose to glucose-6-phosphate with a distinct isoform of hexokinase, hexokinase 1 (HK1) (19).…”

Section: Exploiting Treg Metabolism For Tolerance-inducing Therapiesmentioning

confidence: 99%

Metabolic Pathways Involved in Regulatory T Cell Functionality

et al. 2019

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Regulatory T cells (Treg) are well-known for their immune regulatory potential and are essential for maintaining immune homeostasis. The rationale of Treg-based immunotherapy for treating autoimmunity and transplant rejection is to tip the immune balance of effector T cell-mediated immune activation and Treg-mediated immune inhibition in favor of Treg cells, either through endogenous Treg expansion strategies or adoptive transfer of ex vivo expanded Treg. Compelling evidence indicates that Treg show properties of phenotypic heterogeneity and instability, which has caused considerable debate in the field regarding their correct use. Consequently, for further optimization of Treg-based immunotherapy, it is vital to further our understanding of Treg proliferative, migratory, and suppressive behavior. It is increasingly appreciated that the functional profile of immune cells is highly dependent on their metabolic state. Although the metabolic profiles of effector T cells are progressively understood, little is known on Treg in this respect. The objective of this review is to outline the current knowledge of human Treg metabolic profiles associated with the regulation of Treg functionality. As such information on human Treg is still limited, where information was lacking, we included insightful findings from mouse studies. To assess the available evidence on metabolic pathways involved in Treg functionality, PubMed, and Embase were searched for articles in English indexed before April 28th, 2019 using “regulatory T lymphocyte,” “cell metabolism,” “cell proliferation,” “migration,” “suppressor function,” and related search terms. Removal of duplicates and search of the references was performed manually. We discerned that while glycolysis fuels the biosynthetic and bioenergetic needs necessary for proliferation and migration of human Treg, suppressive capacity is mainly maintained by oxidative metabolism. Based on the knowledge of metabolic differences between Treg and non-Treg cells, we additionally discuss and propose ways of how human Treg metabolism could be exploited for the betterment of tolerance-inducing therapies.

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Section: Exploiting Treg Metabolism For Tolerance-inducing Therapiesmentioning

confidence: 99%

Metabolic Pathways Involved in Regulatory T Cell Functionality

et al. 2019

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“…The G 2 –M phase arrest in multiple myeloma cell lines induced by DCA was reported, and the described effect was supposed to be related to oxidative stress [57,83]. Sodium dichloroacetate causes ROS-dependent T-cell differentiation [84].…”

Section: The Dca Effect On Na–k–2cl Cotransporter and Gendermentioning

confidence: 99%

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

Stakišaitis

Juknevičienė

Damanskienė

et al. 2019

Cancers

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Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells’ mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA’s effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+–K+–2Cl− cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA’s effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.

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“…AZD7545 is a selective inhibitor of PDK2, which inhibits the activity of recombinant PDK and the phosphorylation of intracellular PDH (Makita, Ishiguro, Suzuki, & Nara, ). Moreover, AZD7545 induces ROS production and suppresses Th17‐cell differentiation.…”

Section: Therapeutic Potential Of Warburg Effect In Non‐tumor Diseasesmentioning

confidence: 99%

Involvement of the Warburg effect in non‐tumor diseases processes

Chen

Liu

et al. 2017

Journal Cellular Physiology

131

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Warburg effect, as an energy shift from mitochondrial oxidative phosphorylation to aerobic glycolysis, is extensively found in various cancers. Interestingly, increasing researchers show that Warburg effect plays a crucial role in non-tumor diseases. For instance, inhibition of Warburg effect can alleviate pulmonary vascular remodeling in the process of pulmonary hypertension (PH). Interference of Warburg effect improves mitochondrial function and cardiac function in the process of cardiac hypertrophy and heart failure. Additionally, the Warburg effect induces vascular smooth muscle cell proliferation and contributes to atherosclerosis. Warburg effect may also involve in axonal damage and neuronal death, which are related with multiple sclerosis. Furthermore, Warburg effect significantly promotes cell proliferation and cyst expansion in polycystic kidney disease (PKD). Besides, Warburg effect relieves amyloid β-mediated cell death in Alzheimer's disease. And Warburg effect also improves the mycobacterium tuberculosis infection. Finally, we also introduce some glycolytic agonists. This review focuses on the newest researches about the role of Warburg effect in non-tumor diseases, including PH, tuberculosis, idiopathic pulmonary fibrosis (IPF), failing heart, cardiac hypertrophy, atherosclerosis, Alzheimer's diseases, multiple sclerosis, and PKD. Obviously, Warburg effect may be a potential therapeutic target for those non-tumor diseases.

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Dichloroacetate induces regulatory T-cell differentiation and suppresses Th17-cell differentiation by pyruvate dehydrogenase kinase-independent mechanism

Abstract: Dichloroacetate possesses Treg induction and Th17 suppression, which is independent of PDHK and dependent on ROS production.

Cited by 12 publications

References 27 publications

Metabolic Pathways Involved in Regulatory T Cell Functionality

Metabolic Pathways Involved in Regulatory T Cell Functionality

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

Involvement of the Warburg effect in non‐tumor diseases processes

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