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The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer.Nature Structural & Molecular Biology Mar 2024Three-dimensional (3D) epigenome remodeling is an important mechanism of gene deregulation in cancer. However, its potential as a target to counteract therapy resistance...
Three-dimensional (3D) epigenome remodeling is an important mechanism of gene deregulation in cancer. However, its potential as a target to counteract therapy resistance remains largely unaddressed. Here, we show that epigenetic therapy with decitabine (5-Aza-mC) suppresses tumor growth in xenograft models of pre-clinical metastatic estrogen receptor positive (ER+) breast tumor. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher-order chromatin structure and loss of boundary insulation of topologically associated domains. Significant DNA hypomethylation associates with ectopic activation of ER-enhancers, gain in ER binding, creation of new 3D enhancer-promoter interactions and concordant up-regulation of ER-mediated transcription pathways. Importantly, long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in a loss of ectopic 3D enhancer-promoter interactions and associated gene repression. Our study illustrates the potential of epigenetic therapy to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions, which are associated with the suppression of tumor growth.
Topics: Humans; Female; Breast Neoplasms; Decitabine; Epigenome; DNA Methylation; Chromatin; Epigenesis, Genetic; DNA; Gene Expression Regulation, Neoplastic
PubMed: 38182927
DOI: 10.1038/s41594-023-01181-7 -
PloS One 2024This study aimed to estimate the budget impact of the incorporation of venetoclax for the treatment of patients with Acute Myeloid Leukemia (AML) over 75 years of age or...
OBJECTIVE
This study aimed to estimate the budget impact of the incorporation of venetoclax for the treatment of patients with Acute Myeloid Leukemia (AML) over 75 years of age or those with comorbidities and contraindications for the use of intensive chemotherapy, from the perspective of the social security and the private third-party payers in Argentina.
METHODS
A budget impact model was adapted to estimate the cost difference between the current scenario (azacitidine, decitabine and low doses of cytarabine) and the new scenario (incorporation of venetoclax) for a third-party payer over a time horizon of three years. Input parameters were obtained from a literature review, validated or complemented by expert opinion using a modified Panel Delphi approach. All direct medical costs were estimated by the micro-costing approach and were expressed in US dollars (USD) as of September 2020 (1 USD = 76.18 Argentine pesos).
RESULTS
For a third-party payer with a cohort of 1,000,000 individuals covered, incorporating venetoclax was associated with an average budget impact per-member per-month (PMPM) of $0.11 USD for the social security sector and $0.07 USD for the private sector. The duration of treatment with venetoclax was the most influential parameter in the budget impact results.
CONCLUSION
The introduction of venetoclax was associated with a positive and slight budget impact. These findings are informative to support policy decisions aimed to expand the current treatment landscape of AML.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Argentina; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute; Private Sector; Antineoplastic Agents
PubMed: 38175833
DOI: 10.1371/journal.pone.0295798 -
Cell Transplantation 2024Human embryonic stem cells (hESCs) are advantaged sources for large-scale and homogeneous mesenchymal stem/stromal cells (MSCs) generation. However, due to the...
Human embryonic stem cells (hESCs) are advantaged sources for large-scale and homogeneous mesenchymal stem/stromal cells (MSCs) generation. However, due to the limitations in high-efficiency procedures for hESC-MSCs induction, the systematic and detailed information of mesengenesis and early MSC development are largely obscure. In this study, we took advantage of the well-established twist-related protein 1 (TWIST1)-overexpressing hESCs and two small molecular cocktails (CHIR99021, decitabine) for high-efficient MSC induction. To assess the multidimensional biological and transcriptomic characteristics, we turned to cellular and molecular methods, such as flow cytometry (FCM), quantitative reverse transcription-polymerase chain reaction (qRT-PCR), tri-lineage differentiation, cytokine secretion analysis, transplantation for acute liver injury (ALI) management, and bioinformatics analyses (eg, gene ontology-biological processes [GO-BP], Kyoto Encyclopedia of Genes and Genomes [KEGG], HeatMap, and principal component analysis [PCA]). By combining TWIST1 overexpression (denoted as T) and the indicated small molecular cocktails (denoted as S), hESCs high-efficiently differentiated into MSCs (denoted as TS-MSCs, induced by T and S combination) within 2 weeks. TS-MSCs satisfied the criteria for MSC definition and revealed comparable tri-lineage differentiation potential and ameliorative efficacy upon ALI mice. According to RNA-sequencing (SEQ) analysis, we originally illuminated the gradual variations in gene expression pattern and the concomitant biofunctions of the programmed hESC-MSCs. Overall, our data indicated the feasibility of high-efficient generation of hESC-MSCs by TWIST1 and cocktail-based programming. The generated hESC-MSCs revealed multifaceted and biofunctions as adult BM-MSCs, which collectively suggested promising prospects in ALI management in future.
Topics: Humans; Mice; Animals; Human Embryonic Stem Cells; Mice, SCID; Mice, Inbred NOD; Mesenchymal Stem Cells; Cell Differentiation; Liver; Mesenchymal Stem Cell Transplantation
PubMed: 38173232
DOI: 10.1177/09636897231218383 -
Clinical Epigenetics Jan 2024Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the...
BACKGROUND
Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigenetically silenced genes in cancer by dephosphorylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-tumor efficacy of MC180295, a newly developed CDK9 inhibitor.
METHODS
In this study, we explored the pharmacokinetics of MC180295 in mice and rats, and tested the anti-tumor efficacy of MC180295, and its enantiomers, in multiple cancer cell lines and mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood counts.
RESULTS
MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median IC50 of 171 nM in 46 cell lines representing 6 different malignancies), with the highest potency seen in AML cell lines derived from patients with MLL translocations. MC180295 is a racemic mixture of two enantiomers, MC180379 and MC180380, with MC180380 showing higher potency in a live-cell epigenetic assay. Both MC180295 and MC180380 showed efficacy in in vivo AML and colon cancer xenograft models, and significant synergy with decitabine in both cancer models. Lastly, we found that CDK9 inhibition-mediated anti-tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a significant immune component to the response.
CONCLUSIONS
MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing further toward clinical use.
Topics: Humans; Mice; Rats; Animals; Cyclin-Dependent Kinase 9; Decitabine; DNA Methylation; Cell Line, Tumor; Leukemia, Myeloid, Acute; Apoptosis
PubMed: 38172923
DOI: 10.1186/s13148-023-01617-3 -
Zhongguo Fei Ai Za Zhi = Chinese... Jan 2024Drug resistance is the main cause of high mortality of lung cancer. This study was conducted to investigate the effect of folic acid (FA) on the resistance of non-small...
BACKGROUND
Drug resistance is the main cause of high mortality of lung cancer. This study was conducted to investigate the effect of folic acid (FA) on the resistance of non-small cell lung cancer (NSCLC) cells to Osimertinib (OSM) by regulating the methylation of dual specificity phosphatase 1 (DUSP1).
METHODS
The OSM resistant NSCLC cell line PC9R was establishd by gradually escalation of OSM concentration in PC9 cells. PC9R cells were randomly grouped into Control group, OSM group (5 μmol/L OSM), FA group (600 nmol/L FA), methylation inhibitor decitabine (DAC) group (10 μmol/L DAC), FA+OSM group (600 nmol/L FA+5 μmol/L OSM), and FA+OSM+DAC group (600 nmol/L FA+5 μmol/L OSM+10 μmol/L DAC). CCK-8 method was applied to detect cell proliferation ability. Scratch test was applied to test the ability of cell migration. Transwell assay was applied to detect cell invasion ability. Flow cytometry was applied to measure and analyze the apoptosis rate of cells in each group. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) method was applied to detect the expression level of DUSP1 mRNA in cells. Methylation specific PCR (MSP) was applied to detect the methylation status of the DUSP1 promoter region in each group. Western blot was applied to analyze the expression levels of DUSP1 protein and key proteins in the DUSP1 downstream mitogen-activated protein kinase (MAPK) signaling pathway in each group.
RESULTS
Compared with the Control group, the cell OD450 values (48 h, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of extracellular regulated protein kinases (ERK) were obviously increased (P<0.05); the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the DAC group were obviously increased (P<0.05); the apoptosis rate, the expression of p38 MAPK protein, the phosphorylation level of ERK, and the methylation level of DUSP1 were obviously reduced (P<0.05). Compared with the OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously increased (P<0.05). Compared with the FA+OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM+DAC group were obviously increased; the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously reduced (P<0.05).
CONCLUSIONS
FA may inhibit DUSP1 expression by enhancing DUSP1 methylation, regulate downstream MAPK signal pathway, then promote apoptosis, inhibit cell invasion and metastasis, and ultimately reduce OSM resistance in NSCLC cells.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Dual Specificity Phosphatase 1; Cell Proliferation; p38 Mitogen-Activated Protein Kinases; Methylation; Apoptosis; Cell Line, Tumor
PubMed: 38163975
DOI: 10.3779/j.issn.1009-3419.2023.106.24 -
Journal of Cancer Research and... Dec 2023Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a highly aggressive lymphoma with a poor response to chemotherapy, frequent relapses, low overall... (Review)
Review
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a highly aggressive lymphoma with a poor response to chemotherapy, frequent relapses, low overall survival, and poor prognosis, and is the most common form of PTCL. For relapsed/refractory (R/R) PTCLs, the efficacy of traditional chemotherapy is even worse, so clinical trials and new drugs become their therapeutic hope. The patient was a 43-year-old woman who complained of enlarged superficial lymph nodes (submandibular, neck, axillary, epitrochlear, and groin) and progressive aggravation of skin lesions, facial and limb edema, and subcutaneous masses. Histological analyses of lymph nodes and skin biopsy were suggestive of PTCL-NOS. The patient experienced failure of six lines of therapy, including multiple cycles of chemotherapy, chidamide, and BCL-2 inhibitors therapy, surprisingly, has a good response to PD-1 inhibitor combined with decitabine. We intend to provide some references for clinical practice.
Topics: Female; Humans; Adult; Lymphoma, T-Cell, Peripheral; Decitabine; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38156938
DOI: 10.4103/jcrt.jcrt_1458_22 -
Frontiers in Oncology 2023The aim of this study was to examine the characteristics and prognosis of patients with myelodysplastic syndrome (MDS) accompanied by abnormalities and explore...
The aim of this study was to examine the characteristics and prognosis of patients with myelodysplastic syndrome (MDS) accompanied by abnormalities and explore potential prognostic factors and treatment responses. This retrospective analysis included 95 patients with MDS and abnormalities and 173 patients with MDS without abnormalities at the Fujian Medical University Union Hospital between January 2016 and June 2023. Among patients with abnormalities, 26 (27.4%) developed AML during the disease course, with a median transformation time of 5.7 months. Complex karyotypes were observed in 73.1% of patients, and the proportions of -5 or del(5q), -7 or del(7q), +8, and -20 or del(20q) were 81.8%, 54.5%, 30.7%, and 25.0%, respectively. These patients exhibited poor survival, with a median overall survival (OS) of 7.3 months, and had 1- and 2-year OS rates of 42.2% and 21.5%, respectively. The complete response rates for azacitidine monotherapy, venetoclax combined with azacitidine, decitabine monotherapy, and decitabine combined with low-dose chemotherapy were 9.1%, 41.7%, 37.5%, and 33.3%, respectively. Long-term survival was similar among the four treatment groups. Patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) had a median OS of 21.3 months, which trended to be longer than that of patients who did not undergo allo-HSCT (5.6 months; P = 0.1449). Patients with pulmonary infection at diagnosis experienced worse OS than those without pulmonary infection (2.3 months vs. 15.4 months; P < 0.0001). Moreover, 61.9% of patients with pulmonary infection had immune dysfunction, with a ratio of CD4+ to CD8+ T lymphocytes below two. Pulmonary infections and complex karyotypes were independent adverse prognostic factors for OS. In conclusion, abnormalities in patients with MDS were frequently accompanied by complex karyotypes, and treatments based on hypomethylating agents or venetoclax have limited efficacy. Pulmonary infections associated with immune dysfunction is associated with poor prognosis.
PubMed: 38098502
DOI: 10.3389/fonc.2023.1294037 -
European Review For Medical and... Dec 2023Explore the efficacy of decitabine combined with homoharringtonine + cytarabine + granulocyte colony-stimulating factor (HAG) in the treatment of acute myeloid leukemia...
OBJECTIVE
Explore the efficacy of decitabine combined with homoharringtonine + cytarabine + granulocyte colony-stimulating factor (HAG) in the treatment of acute myeloid leukemia (AML).
PATIENTS AND METHODS
A retrospective analysis of clinical data of 125 patients with AML was done. Of them, 61 patients received a simple HAG treatment (HAG group), and 64 received decitabine combined with an HAG regimen (combined group). Treatment efficacy, immune function before and after the treatment, levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and incidence of adverse reactions in the two groups were compared.
RESULTS
The total response rate of the combined group (84.38%) was higher than that of the HAG group (65.63%) (p < 0.05). After the treatment, levels of CD4+ and CD4+/CD8+ in both groups increased and were significantly higher in the combined group compared to the HAG group. Levels of CD8+, bFGF and VEGF decreased compared to pre-treatment levels and were significantly lower in the combined group than in the HAG group (p < 0.05). There was no significant difference in the rate of adverse reactions between the two groups (p > 0.05).
CONCLUSIONS
Compared to HAG treatment alone, the combination of decitabine and HAG in the treatment of AML is safe, can significantly improve the immune function of the patients, regulate bFGF and VEGF levels, and improve overall treatment efficacy.
Topics: Humans; Decitabine; Vascular Endothelial Growth Factor A; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Treatment Outcome; Leukemia, Myeloid, Acute; Fibroblast Growth Factor 2
PubMed: 38095382
DOI: 10.26355/eurrev_202312_34572 -
Journal of Nippon Medical School =... May 2024Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for...
BACKGROUND
Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin's lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics.
METHODS
Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry.
RESULTS
Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells.
CONCLUSIONS
Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.
Topics: Bendamustine Hydrochloride; Humans; Drug Resistance, Neoplasm; Protein Serine-Threonine Kinases; Polo-Like Kinase 1; Proto-Oncogene Proteins; Cell Line, Tumor; Cell Cycle Proteins; Decitabine; DNA Methylation; Azacitidine; Gene Expression; ATP Binding Cassette Transporter, Subfamily B; Leukemia; Epigenesis, Genetic
PubMed: 38072417
DOI: 10.1272/jnms.JNMS.2024_91-206 -
International Journal of Molecular... Nov 2023Multiple myeloma (MM) is a plasma cell malignancy that accounts for 1% of all cancers and is the second-most-common hematological neoplasm. Bortezomib (BTZ) is a...
Multiple myeloma (MM) is a plasma cell malignancy that accounts for 1% of all cancers and is the second-most-common hematological neoplasm. Bortezomib (BTZ) is a proteasome inhibitor widely implemented in the treatment of MM alone or in combination with other agents. The development of resistance to chemotherapy is one of the greatest challenges of modern oncology. Therefore, it is crucial to discover and implement new adjuvant therapies that can bypass therapeutic resistance. In this paper, we investigated the in vitro effect of methylation inhibitor 5-Aza-2'-deoxycytidine on the proliferative potential of MM cells and the development of resistance to BTZ. We demonstrate that alterations in the DNA methylation profile are associated with BTZ resistance. Moreover, the addition of methylation inhibitor 5-Aza-2'-deoxycytidine to BTZ-resistant MM cells led to a reduction in the proliferation of the BTZ-resistant phenotype, resulting in the restoration of sensitivity to BTZ. However, further in vitro and ex vivo studies are required before adjuvant therapy can be incorporated into existing treatment regimens.
Topics: Humans; Bortezomib; Decitabine; Antineoplastic Agents; Multiple Myeloma; Drug Resistance, Neoplasm; Cell Line, Tumor; Methylation; Apoptosis
PubMed: 38069103
DOI: 10.3390/ijms242316780