Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA309132 | ENA |
REPOSITORIES: ENA
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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).
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:Indolium 1 Exerts Activity against Vemurafenib-Resistant Melanoma In Vivo
| PRJNA827137 | ENA
Project description:Acquired resistance to the BRAF inhibitor vemurafenib remains a major obstacle in melanoma therapy. Drug repurposing offers a promising strategy to overcome such resistance. Here, we investigated the β-blocker propranolol as a sensitizer to vemurafenib in resistant melanoma. Using vemurafenib-resistant cell lines (A375-VR and patient-derived P-8-VR), we found that propranolol restored vemurafenib sensitivity both in vitro and in vivo. RNA sequencing revealed that propranolol significantly upregulated CDK11A and CDK11B. Functional studies demonstrated that knockdown of CDK11 attenuated the pro-apoptotic and cell cycle arrest effects of propranolol and vemurafenib. Mechanistically, propranolol induced G1/S phase arrest and apoptosis without affecting MAPK or AKT pathway reactivation. In a xenograft model, the combination of propranolol and vemurafenib significantly suppressed tumor growth and improved survival. Our study identifies CDK11 upregulation as a novel mechanism by which propranolol reverses vemurafenib resistance, supporting the clinical potential of this drug combination in resistant melanoma.
2026-01-19 | GSE316499 | GEO
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:Whole-exome sequencing was performed on DNA sample extracted from one melanoma cell line resistant to vemurafenib (BRAF V600E inhibitor). The aim of the experiment was to search for genetic alterations responsible for phenotypic diversity of melanoma cell lines reported at the level of cell morphology, activity of signaling pathways essential for melanoma development and progression, and resistance to targeted therapeutics.
2019-07-25 | E-MTAB-8150 | biostudies-arrayexpress
Project description:The development of targeted therapies (Braf/MEK inhibitors) and immunotherapy have had a major impact on the treatment of melanoma. However, the majority of patients with advanced melanomas succumb to their disease. The mechanisms of resistance to both targeted therapies and immunotherapies are numerous and have been well-described. These include the alternative acti-vation of Braf/MEK signaling, novel compensating mutations in additional oncogenes, and loss of neoantigens. There has been limited development of small molecules that target alternative path-ways in melanoma in the last two decades. We have previously identified triphenylmethanes as a class that shows activity against a wide variety of tumors. We have synthesized a novel triphenyl-methane, indolium 1, and demonstrated its efficacy against an aggressive vemurafenib-resistant melanoma in vivo. Indolium 1 has a novel mechanism of action against melanoma, in that it results in induction of the tumor-suppressor EphA3. We believe that pre-IND studies are warranted for this novel compound, given its mechanism of action and ability to inhibit the growth of vemurafenib resistant melanoma in vivo
2022-06-01 | GSE200882 | GEO
Project description:Whole-exome sequencing was performed on DNA samples extracted from seven melanoma cell lines resistant to either vemurafenib (BRAF V600E inhibitor) or trametinib (MEK1/2 inhibitor). The aim of the experiment was to search for genetic alterations responsible for phenotypic diversity of melanoma cell lines reported at the level of cell morphology, activity of signaling pathways essential for melanoma development and progression, and resistance to targeted therapeutics.
2018-10-20 | E-MTAB-7248 | biostudies-arrayexpress
Project description:Whole-exome sequencing was performed on DNA samples extracted from seven melanoma cell lines resistant to either vemurafenib (BRAF V600E inhibitor) or trametinib (MEK1/2 inhibitor). The aim of the experiment was to search for genetic alterations responsible for phenotypic diversity of melanoma cell lines reported at the level of cell morphology, activity of signaling pathways essential for melanoma development and progression, and resistance to targeted therapeutics.
2019-06-15 | E-MTAB-7991 | 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