Similar Datasets
Project description:PARP inhibition and the effect on Arabidopsis thaliana high light tolerance
2012-05-01 | E-MTAB-896 | biostudies-arrayexpress
Project description:Aberrant protein arginine methylation has been observed in multiple cancer types, making it an attractive drug target. Proteins can undergo asymmetric arginine methylation by type I protein arginine methyltransferases (PRMTs), predominately by PRMT1 and to a lesser extent PRMT4, or symmetric arginine methylation by type II PRMTs, predominately PRMT5. Here, we performed targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across cancer cell lines. We found that inhibition of both type I and type II PRMTs suppressed levels of total and phosphorylated ATR protein in cancer cell lines, and down-regulated expression of the ATR gene. Loss of ATR from PRMT inhibition resulted in defective DNA replication stress response activation in following exogenous replication stress. Since PARP inhibitors are known to induce replication stress, we next combined PRMT inhibition with PARP inhibition and found inhibition of PRMT1 or PRMT5 greatly exacerbated PARP inhibitor induced DNA damage. Based on this observation, we assessed the combination of PARP and PRMT inhibition in a panel of cell lines. While inhibition of both type I and type II PRMTs were synergistic with PARP inhibition in both cells with intact and deficient homologous recombination, type I PRMT inhibition resulted in higher toxicity in non-malignant cells. Therefore, we validated the synergy of combined PARP/PRMT5 inhibition in primary patient-derived organoids. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves overall survival in both BRCA-mutant and wild-type patient-derived xenograft models without any detectable hematological toxicities typically associated with PARPi combination therapies. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to improve tumor sensitivity to PARP inhibition. .
2023-10-26 | GSE246325 | GEO
Project description:Poly(ADP-ribose) polymerase 1 (PARP-1) is abnormally expressed in a wide variety of tumors. Emerging evidence suggests that PARP-1 plays key roles in multiple biologic behaviors of tumors, such as modulation of chromatin structure, regulation of gene transcription, tumor proliferation, apoptosis, and angiogenesis, by acting on different molecular pathways. PARP-1 inhibition can achieve a beneficial outcome in tumor treatment. But the specific mechanism of PARP-1 in acute myeloid leukemia (AML) is still to be discovered. We used microarrays to detail the global gene expression in C1498 with and without PARP-1 inhibition and profile differentially expressed genes that might be involved in PARP-1 regulation in AML.
2016-08-31 | GSE64220 | GEO
Project description:The objective of the study is to describe the effects of EtOH on excitatory pre-frontal cortical neuronal ribosomal-engagement (RE) transcripts from total-RNA and provides insights into Poly (ADP-ribose) polymerase (PARP)-mediated regulation of EtOH effects (using the PARP inhibitor ABT-888).
2023-04-13 | GSE227947 | GEO
Project description:Despite numerous therapeutic advances over the years, ovarian cancer, especially high grade serous ovarian carcinoma remains the deadliest gynecological malignancy. Although PARP inhibition has been shown to be an effective (maintenance) therapy for homologous recombination repair deficient or BRCA1 mutated ovarian cancer, there may be further potential for combination therapy with other drugs such as immune checkpoint inhibitors. BRCA1 mutation as well as PARP inhibitor (Olaparib) treatment influenced the activation of immune response pathways such as cGAS-STING signaling and Interferon-alpha response in ovarian cancer cell lines. Bioinformatics functional analyses uncovered further immune related cellular responses and signaling pathways such as JAK-STAT signaling.
2023-08-01 | GSE237361 | GEO
Project description:Specifically, we found inhibition of PARP-1 and PARP-2 catalytic activity, or tissue-specific genetic knockout, results in a severe fertility defect. Transcriptomic analyis uncovered that PARP-1;PARP-2-deficient mice have defects in the progression of stromal cell decidualization manifesting in pregnancy failure
2021-09-13 | GSE169544 | GEO
Project description:Expression data of medulloblastoma patient derived xenograft spheroids upon BGB 290 and romidepsin treatment alone and in combination: Romidepsin and BGB 290 shows synergistic growth inhibition in medulloblastoma patient derived xenograft spheroid models in vitro and in vivo. Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses, and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
2022-02-08 | GSE188894 | GEO
Project description:To examine the immune responses that occur in Brca1-deficent tumors upon olaparib treatment, we performed gene expression analysis of a panel of 4604 cancer and immune-related genes in tumor tissues harvested from Brca1-deficient ovarian tumor-bearing mice after treatment with olaparib or vehicle. Transcriptome analysis showed that the expression of genes associated with immune response, T-cell activation and interferon-gamma(IFNgamma) response were markedly upregulated in tumors treated with olaparib as compared to vehicle. Our data reveal the antitumor immune response of PARP inhibition and demonstrate that it contributes to therapeutic efficacy of PARP inhibition in Brca1-deficient tumors.
2019-02-13 | GSE120500 | GEO
Project description:Deletions or loss-of-function mutations in phosphatase and tensin homolog (PTEN) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. We found that GBM cells lacking PTEN expression are highly sensitive to LMP400, while rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination (HR)-related proteins and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ABC drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting that these drugs should penetrate the BBB. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. In conclusion, our findings provide proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency.
2024-02-14 | GSE225210 | GEO
Project description:Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition
| PRJNA396155 | ENA