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The antifolate pemetrexed induces innate tolerance in human macrophages

ABSTRACT: The antifolate pemetrexed induces innate tolerance in human macrophages

PROVIDER: PRJNA668719 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12809346.fastq.gz	Fastqsanger.gz
	SRR12809347.fastq.gz	Fastqsanger.gz
	SRR12809348.fastq.gz	Fastqsanger.gz
	SRR12809349.fastq.gz	Fastqsanger.gz
	SRR12809350.fastq.gz	Fastqsanger.gz

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The antifolate pemetrexed induces innate tolerance in human macrophages

Project description:Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. GM-CSF drives the generation of human monocyte-derived macrophages with a potent pro-inflammatory activity upon stimulation. One-carbon metabolism (OCM) is a complex network of biosynthetic pathways that includes de novo biosynthesis of purines and thymidylate, amino acid metabolism, and methylation reactions. We explored the molecular impact of blocking OCM with the anti-folate pemetrexed (PMX) on the gene expression profile in LPS-activated GM-CSF-primed human monocyte derived macrophages. The specificity of blocking OCM with the anti-folate PMX was demonstrated with folinic acid.

2021-10-28 | GSE159380 | GEO

Pemetrexed alters inflammatory profile in EA.hy 926 cells grown under low-folate conditions.

2012-10-03 | GSE31986 | GEO

Cytotoxic mechanisms of pemetrexed and HDAC inhibition in non-small cell lung cancer cells involving ribonucleotides in DNA

Project description:The cytotoxic mechanisms of thymidylate synthase inhibitors, such as the multitarget antifolate pemetrexed, are not yet fully understood. Emerging evidence indicates that combining pemetrexed with histone deacetylase inhibitors (HDACi) may enhance therapeutic efficacy in non-small cell lung cancer (NSCLC). To explore this further, A549 NSCLC cells were treated with various combinations of pemetrexed and the HDACi MS275 (Entinostat), and subsequently assessed for cell viability, cell cycle changes, and genotoxic markers. Proteomic alterations were analyzed using label-free shotgun and targeted LC–MS/MS. MS275 enhanced the sensitivity of A549 cells to pemetrexed, but only when administered following prior treatment with pemetrexed. Both HeLa (p53 negative) and A549 (p53 positive) showed robust activation of γH2AX upon treatment with this combination. Importantly, CRISPR/Cas9 knockout of the uracil-DNA glycosylase UNG did not affect γH2AX activation or sensitivity to pemetrexed. Proteomic analysis revealed that MS275 altered the expression of known pemetrexed targets, as well as several proteins involved in pyrimidine metabolism and DNA repair, which could potentiate pemetrexed cytotoxicity. Contrary to the conventional model of antifolate toxicity, which implicates futile cycles of uracil incorporation and excision in DNA, we propose that ribonucleotide incorporation in nuclear and mitochondrial DNA significantly contributes to the cytotoxicity of antifolates like pemetrexed, and likely also of fluorinated pyrimidine analogs. HDAC inhibition apparently exacerbates cytotoxicity of these agents by inhibiting error-free repair of misincorporated ribonucleotides in DNA. The potential of HDACis to modulate pyrimidine metabolism and DNA damage responses offers novel strategies for improving NSCLC outcomes.

2024-12-18 | PXD051824 | Pride

Pemetrexed alters inflammatory profile in EA.hy 926 cells grown under low-folate conditions.

Project description:Pemetrexed is an antifolate drug used in the treatment of lung cancer. EA.hy 926 cells grown under low (Lo) and normal (Hi) folate conditions were treated with PMX. Microarray analysis was used to examine changes in gene expression due to PMX treatment. Hi and Lo cells were grown to confluence and maintained in fresh medium for 24 hours prior to treatment with 0.5uM PMX for 48 hours.

2012-10-03 | E-GEOD-31986 | biostudies-arrayexpress

Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer - The Piedmont Study

Project description:The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic NS-NSCLC treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that the AF-PRS selects for patients with NS-NSCLC that preferentially respond to PMX-PDC, with a goal of providing clinical support for AF-PRS as potential diagnostic test. Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not OS, vs. AF-PRS(-) (16.6 vs. 6.6 mo; p = 0.025). In patients who were Stage I-III patients at time of treatment, PFS, but not OS, was further extended in AF-PRS(+) vs. AF-PRS(-) (36.2 vs. 9.3 mo; p = 0.03). A complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients Stage I-III (6 of 7) and Stage IV (5 of 7) at time of treatment. AF-PRS identified a significant population of patients with extended survival and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.

2023-05-23 | GSE232569 | GEO

Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed

Project description:To test the effects of uracil DNA glycosylase (UNG) loss on the formation of double strand breaks (DSBs) by the anti-cancer agent pemetrexed, we performed ChIP-seq for serine 139-phosphorylated H2AX (gammaH2AX), a marker of DSBs, in human cells wild-type or deficient for UNG in combination with pemetrexed treatment. UNG deficiency results in an increase in DSBs upon pemetrexed treatment, and we found that pemetrexed treatment induces DSBs at different genomic locations in UNG wild-type and knockout cells. Similar results were observed upon cisplatin treatment of UNG wild-type and knockout cells, and the genomic locations of DSBs were distinct between pemetrexed-treated and cisplatin-treated samples. Taken together, our results suggest differential mechanisms for DSB formation in UNG-competent and UNG-deficient cells.

2013-10-28 | GSE50692 | GEO

Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed

Project description:To test the effects of uracil DNA glycosylase (UNG) loss on the formation of double strand breaks (DSBs) by the anti-cancer agent pemetrexed, we performed ChIP-seq for serine 139-phosphorylated H2AX (gammaH2AX), a marker of DSBs, in human cells wild-type or deficient for UNG in combination with pemetrexed treatment. UNG deficiency results in an increase in DSBs upon pemetrexed treatment, and we found that pemetrexed treatment induces DSBs at different genomic locations in UNG wild-type and knockout cells. Similar results were observed upon cisplatin treatment of UNG wild-type and knockout cells, and the genomic locations of DSBs were distinct between pemetrexed-treated and cisplatin-treated samples. Taken together, our results suggst differential mechanisms for DSB formation in UNG-competent and UNG-deficient cells. The genomic distribution of gammaH2AX in UNG WT and KO cells treated with pemetrexed or cisplatin was determined by ChIP-seq

2013-10-28 | E-GEOD-50692 | biostudies-arrayexpress

Transcription profiling by array of mesothelioma pre- and post-resistance biopsies in order to determine a resistance signature to pemetrexed/carboplatin treatment

Project description:Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Innate and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.

2012-10-01 | E-MTAB-1109 | biostudies-arrayexpress

Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer - The Piedmont Study

Project description:Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer - The Piedmont Study

| PRJNA972744 | ENA

Pemetrexed and Erlotinib for Metastatic Colorectal Cancer

Project description:Pemetrexed is a multitargeted antifolate, which primarily inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase in the folate-dependent metabolic process. Nowadays, pemetrexed is used to treat malignant pleural mesothelioma and non-squamous non-small cell lung cancer. Preclinical and clinical studies showed that pemetrexed had cytotoxic activity in many kinds of cancers including colorectal cancer. Erlotinib is a tyrosine-kinase inhibitor of EGFR, which was approved for the treatment of non-small cell lung cancer. Erlotinib also showed activity to colorectal cancer cells. Recently, Zhang et al. demonstrated synergistic cytotoxicity of pemetrexed and gefitinib in preclinical study. In this multicenter, non randomized, open label phase II study, investigators aimed to evaluate the efficacy and safety of Pemetrexed and Erlotinib combination.

| 2211418 | ecrin-mdr-crc

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