Limiting metabolic stress by redirecting glucose flux during in vitro expansion improves efficacy of T cell therapies for cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216666 | GEO | 2023/11/01
REPOSITORIES: GEO
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Project description:The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent. Experiment Overall Design: lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with DCA
2008-06-14 | E-GEOD-6014 | biostudies-arrayexpress
Project description:The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent. Keywords: treatment
2006-10-11 | GSE6014 | GEO
Project description:Myocardial compensatory mechanisms stimulated by reduced oxygen utilization caused by streptozotocin-induced diabetes mellitus (D) and treated with the dichloroacetate (DCA) are presumably associated with the regulation of mitochondria. We aimed to promote the understanding of key signaling pathways and identify effectors involved in signal transduction.
2022-04-18 | PXD033256 | Pride
Project description:Peripheral neuropathy (PN) is a debilitating side effect of many pharmaceutical agents and is among the most common reasons why patients stop their treatment early. Dichloroacetate (DCA) is a therapeutic drug that inhibits the pyruvate dehydrogenase complex (PDC), thereby modulating metabolic flux in cells. Despite success in improving outcomes of disease, reversible PN has been the single factor limiting the therapeutic potential for DCA. As a result, clinical trials for the drug have been halted prematurely. Establishing toxicity pathways in cells of the peripheral nervous system (PNS) that are involved in DCA-induced PN would provide new opportunities to intervene and mitigate adverse side effects associated with DCA. We investigated the molecular mechanisms underlying DCA-induced injury to both glial and neuronal cells. It was hypothesized that SCs would show activated transcriptional responses associated with oxidative damage and apoptosis at therapeutic doses while these responses will be absent or reduced in DRGs. Experiments were expected to pinpoint molecular mechanisms underlying DCA-induced neurotoxicity, and to reveal the window of therapeutic intervention to reduce side effects associated with DCA in clinical settings.
2024-04-27 | GSE218812 | GEO
Project description:The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36. Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo. Tumors from animals treated with control vehicle, honokiol DCA, and hexafluoro were harvested and snapped-frozen in liquid nitrogen until RNA Extraction. RNA extraction was performed according to the Qiagen RNeasy kit. RNA samples were then submitted to Emory Universityâs Intergrated Genomics Core for RNA quality analysis and gene expression assay. Gene expression analysis was performed using an Illumina HumanHT-12 v3 Expression Bead Chip and Gene Expression Module of Illuminaâs GenomeStudio Software package (v2011.1, Illumina).
2016-01-20 | E-GEOD-76956 | biostudies-arrayexpress
Project description:The majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas. Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active. Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36. Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo.
2016-01-20 | GSE76956 | GEO
Project description:Dichloroacetate (DCA) prevents cisplatin-induced nephrotoxicity without compromising its anti-cancer properties.
| PRJNA286100 | ENA
Project description:Honokiol Bis-Dichloroacetate (Honokiol DCA) Demonstrates Activity in Vemurafenib-Resistant Melanoma in Vivo.
| PRJNA309132 | ENA
Project description:Anaerobic degradation of dichloroacetate (DCA) in the environment is not well understood. Recently, a microbial mixed culture (RM) was derived from pristine freshwater sediment enriched with dichloromethane (CH2Cl2, DCM) as the sole energy source under anoxic conditions. RM comprises of Candidatus Dichloromethanomonas elyunquensis strain RM which cannot only utilize DCM as an energy source, but also DCA, with the transient formation of formate, H2, and carbon monoxide (CO). To understand the metabolic capabilities of Ca. Dichloromethanomonas elyunquensi, a comparative global proteomic analysis between DCA-grown (MS datasets 1,2,3 - T8,T15) and DCM-grown (MS datasets 4,5,6 - T12,T15) cells was performed. Differential protein expression analysis identified enzymes catalyzing the conversion of DCA to acetyl-coenzyme A (CoA) via glyoxylate as well as enzymes of the Wood-Ljungdahl pathway in DCA fermentation. Combined with physiological, biochemical, and genomics information, these results demonstrate the involvement of a haloacid dehalogenase and the Wood-Ljungdahl pathway in the anaerobic metabolism of DCA, which has broader implications in our understanding of DCA turnover in natural and engineered environments.
2020-11-25 | MSV000086520 | MassIVE
Project description:Using the highly sensitive miRNA array, we screened out different microRNAs regulated by different concertration of dichloroacetate for different time. Among them 119 microRNAs were obvious Metabolic abnormality is one of the hallmarks of cancer and has been shown to be involved in chemoresistance. In this context, targeting the abnormal metabolism of cancer cells has been an intense avenue of research aiming at asphyxiating the tumor . DCA inhibits the enzymatic activity of Pyruvate Dehydrogenase Kinases (PDK 1 to 4), which are enzymes critical for the activation of the pyruvate dehydrogenase necessary to transform pyruvate into acetyl-CoA, linking the glycolytic metabolism to the citric acid cycle. DCA is primarily used to treat lactic acidosis and hereditary mitochondrial disease, which has been also reported to have anti-cancer effect . However, the mechanism underlying the effect of DCA on CRC treatment remain unsettled. Multiple and complex mechanisms have been described that control the metabolic shift in cancer cells, including microRNAs (miRNAs). MicroRNAs represents a class of small endogenous noncoding RNAs that regulate translation and degradation of mRNAs. Besides controlling the metabolism, miRNAs participate in many more biological processes including cell proliferation, migration, apoptosis , self-renewal, initiation and development of cancers, and chemoresistance.Here we explore the molecular mechanism involved in regulating glucose metabolism and associated chemotherapy resistance in CRC. By exploiting DCA, pyruvate dehydrogenase kinase (PDK) inhibitor, in CRC cells, trying to elucidate the roles of related miRNAs and thereby outlining a signaling pathway.
2021-01-01 | GSE125309 | GEO