Antitumor activity of dichloroacetate on C6 glioma cell: in vitro and in vivo evaluation

Yu, De‐Quan; Zhao, Xin; Ren, Wei; Wang, Xin; Yu, Kefu; Li, Dan; Zhang, Xuan; Zhang, Qiang

doi:10.2147/ott.s40992

Cited by 25 publications

(20 citation statements)

References 48 publications

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“…In the present study, the IC 50 values of DCA are relatively high (≥20 mM, 72 hr) to halt the proliferation of GBM cells in culture, which is consistent with most of the studies in vitro [ 13 , 23 , 24 , 39 - 43 ]. On the other hand, in vivo studies testing DCA on pre-clinical rodent models with different types of malignancy demonstrated encouraging results with effective doses of 50–200 mg/kg/day [ 39 , 40 , 44 ], which translates into approximately 13 kg/kg/day in human resulting in the serum level of 0.5-1 mM [ 15 , 40 ]. Therefore, the in vivo achievable concentration (0.5-1 mM) may not necessarily be correlated with the supraphamacological level (5–50 mM) tested in vitro for this anti-metabolic compound.…”

Section: Discussionsupporting

confidence: 92%

Dual-targeting of aberrant glucose metabolism in glioblastoma

Shen

Decollogne

Dilda

et al. 2015

J Exp Clin Cancer Res

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BackgroundGlioblastoma (GBM) is the most common and malignant primary brain tumor. In contrast to some other tumor types, aberrant glucose metabolism is an important component of GBM growth and chemoresistance. Recent studies of human orthotopic GBM in mice and in situ demonstrated GBM cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. These observations suggest that the homeostasis of energy metabolism of GBM cells might be further disturbed by dual-inhibition of glucose metabolism. The present study aimed to evaluate the efficacy and the mechanisms of dual-targeting therapy in GBM cells.MethodsRepresentative GBM cells (immortalized GBM cell lines and patient-derived GBM cells) and non-cancerous cells were treated with 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), an in-house designed novel arsenic-based mitochondrial toxin, in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor. The efficacy of this combinatorial therapy was evaluated by MTS assay, clonogenic surviving assay and apoptotic assays. The underlying mechanisms of this dual-targeting treatment were unraveled by using mitochondrial membrane potential measurements, cytosol/mitochondrial ROS detection, western blotting, extracellular flux assay and mass spectrometry.ResultsAs monotherapies, both PENAO and DCA induced proliferation arrest in a panel of GBM cell lines and primary isolates. PENAO inhibited oxygen consumption, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis. By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells), impair the clonogenicity, and induce mitochondria-mediated apoptosis. An oxidative stress of mitochondrial origin takes a prominent place in the mechanism by which the combination of PENAO and DCA induces cell death. Additionally, PENAO-induced oxidative damage was enhanced by DCA through glycolytic inhibition which in turn diminished acid production induced by PENAO. Moreover, DCA treatment also led to an alteration in the multidrug resistance (MDR) phenotype of GBM cells, thereby leading to an increased cytosolic accumulation of PENAO.ConclusionsThe findings of this study shed a new light with respect to the dual-targeting of glucose metabolism in GBM cells and the innovative combination of PENAO and DCA shows promise in expanding GBM therapies.

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Section: Discussionsupporting

confidence: 92%

Dual-targeting of aberrant glucose metabolism in glioblastoma

Shen

Decollogne

Dilda

et al. 2015

J Exp Clin Cancer Res

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“…In 2017, a study on flow-induced metabolic reprogramming in ECs reported that HIF-1α increased PDK-1, which reduced mitochondrial respiratory capacity [ 10 ]. On cancer cells from various origins, it has been shown that DCA, a PDK inhibitor currently studied in clinical trials, decreased HIF-1 activity, resulting in a reduced expression of HIF-1α target genes including pro-angiogenic factors [ 11 , 12 ] and a decreased tumor angiogenesis [ 12 , 13 , 14 , 15 , 16 ]. To our knowledge, besides this HIF-1α mediated effect by cancer cells, a direct effect of DCA through a metabolic reprogramming of ECs has not been previously considered.…”

Section: Introductionmentioning

confidence: 99%

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Schoonjans

Mathieu

Joudiou

et al. 2020

JCM

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Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.

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“…It has also been recently been tested in phase I clinical trials to treat patients with advanced solid tumors [15] , [16] . DCA exhibits potent anti-cancer activity in cancer cells [17] , [18] and animal models [12] , [19] , [20] , via inducing oxidative stress that causes apoptosis in cancer cells [21] , [22] . Similarly, DCA exhibited protective effects on hypoxia-induced pulmonary hypertension via inducing apoptosis of the pulmonary smooth muscle cells [23] , [24] .…”

Section: Introductionmentioning

confidence: 99%

AKT-independent activation of p38 MAP kinase promotes vascular calcification

et al. 2018

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Vascular calcification is prevalent in patients with atherosclerosis, and oxidative stress promotes pathogenesis of atherosclerosis. We have previously reported that activation of AKT by oxidative stress induces vascular calcification. Using sodium dichloroacetate (DCA), a previously reported small molecule inhibitor of AKT, the present studies uncovered an AKT-independent mechanism in regulating vascular calcification.We found that DCA dose-dependently induced calcification of vascular smooth muscle cells (VSMC) in vitro and aortic rings ex vivo. Furthermore, DCA markedly enhanced vascular calcification in atherosclerotic ApoE knockout mice in vivo. DCA-induced VSMC calcification was associated with increased Runx2, but not via activation of AKT, a key upstream signal that upregulates Runx2 during VSMC calcification. In contrast, DCA inhibited AKT activation and induced activation of p38 MAPK in calcified atherosclerotic lesions in vivo and calcified VSMC in vitro. Using a pharmacological inhibitor and shRNA for p38 MAPK, we demonstrated that inhibition of p38 MAPK blocked DCA-induced Runx2 upregulation and VSMC calcification. Furthermore, Runx2 deletion attenuated DCA-induced VSMC calcification. Immunoprecipitation analysis revealed association of p38 MAPK with Runx2, which was enhanced by DCA treatment. Knockdown p38 MAPK inhibited DCA-induced Runx2 transactivity, supporting the function of p38 MAPK in regulating Runx2 transactivity.Our studies have uncovered a new function of DCA in regulating vascular calcification, via AKT-independent activation of p38 MAPK. Furthermore, we have identified novel interaction between p38 MAPK and Runx2 enhances Runx2 transactivity, thus promoting VSMC calcification. These results revealed a novel signaling mechanism underlying DCA-induced vascular calcification, and offer opportunities to identify new therapeutic targets.

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Antitumor activity of dichloroacetate on C6 glioma cell: in vitro and in vivo evaluation

Cited by 25 publications

References 48 publications

Dual-targeting of aberrant glucose metabolism in glioblastoma

Dual-targeting of aberrant glucose metabolism in glioblastoma

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

AKT-independent activation of p38 MAP kinase promotes vascular calcification

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