Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Dichloroacetate (DCA) prevents cisplatin-induced nephrotoxicity without compromising its anti-cancer properties.

ABSTRACT: The aim of this study was to compare the transcriptional changes that occur in the kidneys of mice administered cisplatin or DCA, or both, by RNA-seq. generation of RNA-seq datasets from mice subjected to 4 different treatments. 3 biological replicates per treatment. Saline treatment is control.

ORGANISM(S): Mus musculus

SUBMITTER: Kristine Hardy

PROVIDER: E-GEOD-69652 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties.

Galgamuwa Ramindhu R Hardy Kristine K Dahlstrom Jane E JE Blackburn Anneke C AC Wium Elize E Rooke Melissa M Cappello Jean Y JY Tummala Padmaja P Patel Hardip R HR Chuah Aaron A Tian Luyang L McMorrow Linda L Board Philip G PG Theodoratos Angelo A

Journal of the American Society of Nephrology : JASN 20160309 11

Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated ...[more]

PMID: 26961349

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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).

Dataset Information

Dichloroacetate (DCA) prevents cisplatin-induced nephrotoxicity without compromising its anti-cancer properties.

Publications

Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties.

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