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Chidamide and Anlotinib act synergistically in Jurkat cells by inhibiting the Hippo signaling pathway

ABSTRACT: T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic malignancy characterized by drug resistance, relapse and poor prognosis. Chidamide, a histone deacetylase inhibitor, has shown epigenetic therapeutic potential in T-ALL, but its efficacy is limited and acquired drug resistance exists. To overcome these limitations, we systematically evaluated the synergistic Combination effects of three drug candidates, OTX-015 (BET inhibitor), Metformin (metabolic regulator), and Anlotinib (multitargeted tyrosine kinase inhibitor), with Chidamide.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310869 | GEO | 2025/11/24

REPOSITORIES: GEO

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Chidamide and Anlotinib Synergistically Inhibit High Grade B-Cell Lymphomas via PI3K/AKT Signaling Pathway

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RNA-seq of NK-92 cell line upon BET inhibitor treatment (OTX-015)

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Chidamide and Anlotinib Synergistically Inhibit High Grade B-Cell Lymphomas via PI3K/AKT Signaling Pathway

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Project description:Further to our previous study (E-MTAB-5997), here we performed transcriptome profiling on Anlotinib-resistant NCI-H1975 and Anlotinib-treated Anlotinib-resistant NCI-H1975, and would like to understand the effects of Anlotinib on Anlotinib-resistant NCI-H1975 cell, compare the different transcriptome profiling on NCI-H1975 cells and Anlotinib-resistant NCI-H1975 cells, sought to find the biomarker for explaining Anlotinib resistance.

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Role of different epigenetic drugs in reshaping murine melanoma tumor microenvironment

Project description:To highlight the role of epigenetics in immune responses, we exploited a model of melanoma using B16F10 injected subcutaneously in syngeneic C57black6j mice and studied the effect of inhibitors of (i) BET bromodomain (OTX-015) (ii) DNA methyltransferase (DNMT) (guadecitabine) on in vivo tumour growth. OTX-015 showed significant in vivo effects in reducing tumour growth in our setting. Guadecitabine induced MHC class I expression on tumour cells, but the latter also increased immune checkpoint expression on cancer cells. Each epigenetic agent altered the tumour microenvironment (TME), mostly by reducing immune suppression, particularly of Tregs or MDSC, or both. OTX-015 and guadecitabine had strong effects, but in opposite ways. OTX-015 downmodulated antitumour responses, whereas guadecitabine remodeled the TME to be more immune-responsive. Epigenetic therapy may enhance immunotherapy, but specific schedules for treatments need to be studied for each drug. Among the drugs tested, guadecitabine seems to be the most promising drug for successful combination immunotherapy.

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Role of different epigenetic drugs in reshaping murine melanoma tumor microenvironment [Array]

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CREBBP cooperates with cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory DLBCL

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Transcriptome profiling of HCC1937 vector and wtBRCA1 cell lines which were treated with OTX-015

Project description:Purpose: To compare the transcriptomes of HCC1937 vector and wtBRCA1 cells which were treated with OTX-015. Methods: HCC1937 vector and wtBRCA1 cells were treated with 5 micromolar OTX-015 for 24 hours. Total RNA was extracted and processed with NEBNext Ultra Directional RNA Library Prep Kit for cDNA library preparation. The data are in duplicate and raw data were generated by Illumina 2500 sequencer. The Fastq format data were then processed with Tophat for genome mapping. After getting the bam files, they were further analyzed with cuffdiff for gene expression of different groups. Results: From the transcriotome profiling and analysis, we got gene expression data of DMSO control group and OTX-015 treatment group for the HCC1937 BRCA1 isogenic cell lines. Conclusion: The gene expression data revealed the transcriptome variation by OTX-015 treatment.

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Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B cell lymphoma

Project description:Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapies of these patients. A new oral histone deacetylase inhibitor, chidamide shows anti-tumor activity by activating the pro-apoptosis pathway in some other hematological malignancies, suggesting its potential application to the relapsed and refractory B cell lymphoma. In this study, we examined the therapeutic effects of chidamide on the cell and mouse models of the rituximab/chemotherapy resistant B cell lymphoma, as well as the primary B cell lymphoma cells. In Raji-4RH and RL-4RH cells, the rituximab/chemotherapy resistant B cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest, which were associated with E2F1/2 inactivation and CDK2 degradation. The primary B cell lymphoma cells from Rituximab/chemotherapy relapsed and refractory patients were also very sensitive to chidamide treatment. Interestingly, chidamide triggered the cell death via the autophagy pathway instead of the activation of apoptosis in Raji-4RH and RL-4RH cells, likely due to the lack of the pro-apoptotic proteins in these resistant cells. In the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as the direct target genes of chidamide, which control the autophagy and cell cycle respectively in RRCL treated with chidamide. Moreover, the combination of chidamide with the chemotherapy drug Cisplatin sensitized the RRCL to growth inhibition in a synergistic manner. Chidamide-Cisplatin combination significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, our studies provides a theoretic and mechanistic basis for further evaluation of the chidamide-based clinical trial for rituximab/chemotherapy relapsed and refractory B cell lymphoma patients.

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Aberrant JAK-STAT pathway confers resistance to the HDAC inhibitor chidamide in Natural Killer/T-cell lymphoma through chromatin remodeling

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