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Medical Oncology (Northwood, London,... Jul 2022Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and...
BACKGROUND
Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERβ agonist DPN on ERα and ERβ re-expressions in the MDA-MB-231 cells as a model of TNBC.
METHODS
Using MTT assay, the IC of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERβ gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed.
RESULTS
Both ERα and ERβ mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERβ activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells.
CONCLUSIONS
The antiproliferative effect of ERβ could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.
Topics: Humans; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Decitabine; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogen Receptor beta; Insulin-Like Growth Factor I; Nitriles; Propionates; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Vorinostat
PubMed: 35843988
DOI: 10.1007/s12032-022-01765-1 -
Scientific Reports Jan 2021Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in...
Design and development of efficient processes for continuous manufacturing of solid dosage oral formulations is of crucial importance for pharmaceutical industry in order to implement the Quality-by-Design paradigm. Supercritical solvent-based manufacturing can be utilized in pharmaceutical processing owing to its inherent operational advantages. However, in order to evaluate the possibility of supercritical processing for a particular medicine, solubility measurement needs to be carried out prior to process design. The current work reports a systematic solubility analysis on decitabine as an anti-cancer medicine. The solvent is supercritical carbon dioxide at different conditions (temperatures and pressures), while gravimetric technique is used to obtain the solubility data for decitabine. The results indicated that the solubility of decitabine varies between 2.84 × 10 and 1.07 × 10 mol fraction depending on the temperature and pressure. In the experiments, temperature and pressure varied between 308-338 K and 12-40 MPa, respectively. The solubility of decitabine was plotted against temperature and pressure, and it turned out that the solubility had direct relation with the pressure due to the effect of pressure on solvating power of solvent. The effect of temperature on solubility was shown to be dependent on the cross-over pressure. Below the cross-over pressure, there is a reverse relation between temperature and solubility, while a direct relation was observed above the cross-over pressure (16 MPa). Theoretical study was carried out to correlate the solubility data using several thermodynamic-based models. The fitting and model calibration indicated that the examined models were of linear nature and capable to predict the measured decitabine solubilities with the highest average absolute relative deviation percent (AARD %) of 8.9%.
Topics: Antineoplastic Agents; Carbon Dioxide; Decitabine; Models, Theoretical; Solubility; Thermodynamics
PubMed: 33441880
DOI: 10.1038/s41598-020-80399-7 -
Neurosurgical Review Aug 2022Treatment of meningiomas refractory to surgery and irradiation is challenging and effective chemotherapies are still lacking. Recently, in vitro analyses revealed...
Treatment of meningiomas refractory to surgery and irradiation is challenging and effective chemotherapies are still lacking. Recently, in vitro analyses revealed decitabine (DCT, 5-aza-2'-deoxycytidine) to be effective in high-grade meningiomas and, moreover, to induce hypomethylation of distinct oncogenes only sparsely described in meningiomas in vivo yet.Expression of the corresponding onco- and tumor suppressor genes TRIM58, FAM84B, ELOVL2, MAL2, LMO3, and DIO3 were analyzed and scored by immunohistochemical staining and RT-PCR in samples of 111 meningioma patients. Correlations with clinical and histological variables and prognosis were analyzed in uni- and multivariate analyses.All analyzed oncogenes were highly expressed in meningiomas. Expression scores of TRIM58 tended to be higher in benign than in high-grade tumors 20 vs 16 (p = .002) and all 9 samples lacking TRIM58 expression displayed WHO grade II/III histology. In contrast, median expression scores for both FAM84B (6 vs 4, p ≤ .001) and ELOVL2 (9 vs 6, p < .001) were increased in high-grade as compared to benign meningiomas. DIO3 expression was distinctly higher in all analyzed samples as compared to the reference decitabine-resistant Ben-Men 1 cell line. Increased ELOVL2 expression (score ≥ 8) correlated with tumor relapse in both uni- (HR: 2.42, 95%CI 1.18-4.94; p = .015) and multivariate (HR: 2.09, 95%CI 1.01-4.44; p = .046) analyses.All oncogenes involved in DCT efficacy in vitro are also widely expressed in vivo, and expression is partially associated with histology and prognosis. These results strongly encourage further analyses of DCT efficiency in meningiomas in vitro and in situ.
Topics: Decitabine; Humans; Meningeal Neoplasms; Meningioma; Neoplasm Recurrence, Local; Oncogenes; Prognosis
PubMed: 35445910
DOI: 10.1007/s10143-022-01789-1 -
Cancer Research and Treatment Oct 2023Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin's lymphoma that affects the brain, eyes, cerebrospinal fluid, or spinal cord without...
Long-term Complete Remission of Decitabine-Primed Tandem CD19/CD22 CAR-T Therapy with PD-1 and BTK Inhibitors Maintenance in a Refractory Primary Central Nervous System Lymphoma Patient.
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin's lymphoma that affects the brain, eyes, cerebrospinal fluid, or spinal cord without systemic involvement. The outcome of patients with PCNSL is worse compared to patients with systemic diffuse large B-cell lymphoma. Given potential mortality associated with severe immune effector cell-associated neurotoxicity syndrome (ICANS), patients with PCNSL have been excluded from most clinical trials involving chimeric antigen receptor T-cell (CAR-T) therapy initially. Here, we report for the first time to apply decitabine-primed tandem CD19/CD22 dual-targeted CAR-T therapy with programmed cell death-1 (PD-1) and Bruton's tyrosine kinase (BTK) inhibitors maintenance in one patient with multiline-resistant refractory PCNSL and the patient has maintained complete remission (CR) for a 35-month follow-up period. This case represents the first successful treatment of multiline resistant refractory PCNSL with long-term CR and without inducing ICANS under tandem CD19/CD22 bispecific CAR-T therapy followed by maintenance therapy with PD-1 and BTK inhibitors. This study shows tremendous potential in the treatment of PCNSL and offers a look toward ongoing clinical studies.
Topics: Humans; Adaptor Proteins, Signal Transducing; Brain; Central Nervous System Neoplasms; Decitabine; Lymphoma, Non-Hodgkin; Programmed Cell Death 1 Receptor; Receptors, Chimeric Antigen; Sialic Acid Binding Ig-like Lectin 2; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors
PubMed: 37321275
DOI: 10.4143/crt.2023.371 -
Clinical Epigenetics Aug 2019DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable...
BACKGROUND
DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable pharmacokinetics with the current DNA-demethylating agents, azacitidine (AZA) and decitabine (DAC), because of their rapid deamination by cytidine deaminase in vivo and spontaneous hydrolytic cleavage. Here, we aimed to develop metabolically stable prodrugs of AZA and DAC as novel DNA-demethylating agents.
RESULTS
Thirty-five 5'-O-trialkylsilylated AZAs/DACs were synthesized with potential resistance to deamination. Out of these, 11 compounds exhibited demethylating activity similar to that of DAC and guadecitabine, and a suitable aqueous solubility. Pharmacokinetic analysis in mice showed that OR-2003 displayed the highest serum concentration and the area under the curve in an intraperitoneal experiment, whereas OR-2100 exhibited high stability to cytidine deaminase. Treatment of cells with OR-2003 and OR-2100 depleted DNA methyltransferase 1 completely and induced both gene-specific and genome-wide demethylation. The treatment suppressed the growth of multiple types of cancer cells and induced re-expression of tumor suppressor genes. The anti-tumor effect and DNA demethylation effect of OR-2003 and OR-2100 were comparable to that of DAC with fewer adverse effects in vivo.
CONCLUSIONS
We developed two novel prodrugs of DAC that exhibited greater stability, comparable DNA demethylation activity, and less toxicity. These compounds are expected to overcome the difficulty in achieving stable pharmacokinetics in patients, leading to maximum DNA demethylation activity with minimum adverse effects.
Topics: Animals; Area Under Curve; Azacitidine; Blood Chemical Analysis; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Methylation; Decitabine; Drug Stability; Gene Expression Regulation, Neoplastic; Injections, Intraperitoneal; Mice; Neoplasms; Prodrugs; Xenograft Model Antitumor Assays
PubMed: 31370878
DOI: 10.1186/s13148-019-0709-y -
Cancer Control : Journal of the Moffitt... 2022The prototype DNA hypomethylating agents 5-azacytidine (5AC) and decitabine (DAC) are currently FDA-approved for treatment of blood and bone marrow disorders like...
INTRODUCTION
The prototype DNA hypomethylating agents 5-azacytidine (5AC) and decitabine (DAC) are currently FDA-approved for treatment of blood and bone marrow disorders like myelodysplastic syndrome. 5AC and DAC are considered similar drugs and were shown to induce histone modifications that modulate gene expression. The aim of this study is to compare the effect of both drugs on histone acetylation and methylation at multiple histone amino acids residues.
METHODS
Mass spectrometry was used to compare the effect of both drugs on 95 different histone posttranslational modifications (PTMs) in leukemia cells. ChIP-Seq analysis was used to compare the impact of both drugs on the genome-wide acetylation of the H3K9 mark using primary leukemia cells from six de-identified AML patients.
RESULTS
Both DAC and 5AC induced histone PTMs in different histone isoforms like H1.4, H2A, H3, H3.1, and H4. Changes in both histone methylation and acetylation were observed with both drugs; however, there were distinct differences in the histone modifications induced by the two drugs. Since both drugs were shown to increase the activity of the HDAC SIRT6 previously, we tested the effect of 5AC on the acetylation of H3K9, the physiological substrate SIRT6, using ChIP-Seq analysis and compared it to the previously published DAC-induced changes. Significant H3K9 acetylation changes (< .05) were detected at 925 genes after 5AC treatment vs only 182 genes after DAC treatment. Nevertheless, the gene set modified by 5AC was different from that modified by DAC with only ten similar genes modulated by both drugs.
CONCLUSION
Despite similarity in chemical structure and DNA hypomethylating activity, 5AC and DAC induced widely different histone PTMs and considering them interchangeable should be carefully evaluated. The mechanism of these histone PTM changes is not clear and may involve modulation of the activity or the expression of the enzymes inducing histone PTMs.
Topics: Acetylation; Azacitidine; Cell Line, Tumor; DNA Methylation; Decitabine; Histones; Humans; Leukemia; Protein Processing, Post-Translational
PubMed: 35067084
DOI: 10.1177/10732748221074051 -
International Journal of Biological... Nov 2021SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein...
SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.
Topics: Adaptor Proteins, Signal Transducing; COVID-19; Coronavirus Nucleocapsid Proteins; DNA Helicases; Decitabine; Drug Delivery Systems; Genomics; Imatinib Mesylate; Molecular Docking Simulation; Molecular Dynamics Simulation; Phosphoproteins; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; RNA-Binding Proteins; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34517025
DOI: 10.1016/j.ijbiomac.2021.09.018 -
Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma.Leukemia Jun 2022Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL,...
Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
Topics: Azacitidine; Decitabine; Genomics; Humans; Lymphoma, T-Cell, Peripheral; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Neutropenia; Treatment Outcome
PubMed: 35459873
DOI: 10.1038/s41375-022-01571-8 -
Journal of Oncology Pharmacy Practice :... Jun 2024To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the... (Review)
Review
Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review.
OBJECTIVE
To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use.
DATA SOURCES
Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy.
DATA SUMMARY
Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20 mg/m and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030.
CONCLUSIONS
Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.
Topics: Humans; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Administration, Oral; Azacitidine; Decitabine; Antimetabolites, Antineoplastic; Uridine
PubMed: 38509812
DOI: 10.1177/10781552241238979 -
Frontiers in Immunology 2022Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40%...
Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin's lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined =0.021 and undefined versus undefined =0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months < 0.0001 and undefined versus 2.0months <0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined <0.0001 and 1.7 months versus undefined =0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.
Topics: Cytokine Release Syndrome; Decitabine; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; Sialic Acid Binding Ig-like Lectin 2
PubMed: 36059523
DOI: 10.3389/fimmu.2022.969660