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Effects of dichloroacetate on transcriptional networks in rat Schwann cells and primary sensory neurons

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE218812 | GEO | 2024/04/27

REPOSITORIES: GEO

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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).

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Effects of dichloroacetate on transcriptional networks in rat Schwann cells and primary sensory neurons

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