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Cold Spring Harbor Perspectives in... May 2017Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to... (Review)
Review
Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; DNA Demethylation; Decitabine; Humans; Neoplasms; Tumor Microenvironment
PubMed: 28159832
DOI: 10.1101/cshperspect.a026948 -
Blood Dec 2022
Topics: Humans; Qi; Purpura, Thrombocytopenic, Idiopathic; Decitabine; Myeloid-Derived Suppressor Cells; Thrombocytopenia
PubMed: 36580341
DOI: 10.1182/blood.2022018373 -
Clinical and Translational Medicine Jul 2023The first-line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long-term responses remains challenging....
BACKGROUND
The first-line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long-term responses remains challenging. Low-dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP.
METHODS
The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg-1, DNMT3b and NLRP3, together with IL-10 plasma levels was measured to examine its function. Bisulfite-sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh-PPARγ THP-1 cell line was created to verify if low-dose DAC-modulated M2 macrophage polarization was PPARγ-dependent. The passive ITP models were used to investigate the therapeutic effects of low-dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ.
RESULTS
The M2 monocytes with impaired immunoregulation were observed in ITP. After high-dose dexamethasone (HD-DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg-1 and IL-10 in CR patients. Low-dose DAC promoted M2 macrophage polarization in a PPARγ-dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low-dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine-tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome.
CONCLUSIONS
Low-dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP.
Topics: Animals; Mice; PPAR gamma; Decitabine; Interleukin-10; Inflammasomes; Leukocytes, Mononuclear; NLR Family, Pyrin Domain-Containing 3 Protein; Purpura, Thrombocytopenic, Idiopathic; Macrophages
PubMed: 37488670
DOI: 10.1002/ctm2.1344 -
Science Translational Medicine Aug 2023Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury...
Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury and high mortality in aged mice after sepsis challenge were attributable to impaired endothelial regeneration and vascular repair. Genetic lineage tracing study showed that endothelial regeneration after sepsis-induced vascular injury was mediated by lung resident endothelial proliferation in young adult mice, whereas this intrinsic regenerative program was impaired in aged mice. Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic expression or in vivo endothelium-targeted nanoparticle delivery of the gene driven by an endothelial cell (EC)-specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. Mechanistically, aging-induced promoter hypermethylation in mice, which could be inhibited by decitabine treatment, inhibited induction after sepsis challenge. In COVID-19 lung autopsy samples, was not induced in vascular ECs of elderly patients in their 80s, in contrast with middle-aged patients (aged 50 to 60 years). Thus, reactivation of FoxM1-mediated endothelial regeneration and vascular repair may represent a potential therapy for elderly patients with ARDS.
Topics: Animals; Mice; COVID-19; Decitabine; Endothelium, Vascular; Forkhead Box Protein M1; Lung; Lung Injury; Mice, Transgenic; Regeneration; Respiratory Distress Syndrome; Sepsis
PubMed: 37585502
DOI: 10.1126/scitranslmed.abm5755 -
Blood Advances Apr 2021Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA... (Review)
Review
Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA hypomethylating agents (HMAs), have been a mainstay in the treatment of higher-risk myelodysplastic syndromes. The development of oral HMAs has been an area of active interest; however, oral bioavailability has been quite poor due to rapid metabolism by cytidine deaminase (CDA). This led to the development of the novel CDA inhibitor cedazuridine, which was combined with an oral formulation of decitabine. Preclinical work demonstrated a pharmacokinetic and pharmacodynamic profile approximate to parenteral decitabine, leading to early-phase clinical trials of oral cedazuridine-decitabine (C-DEC) in myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). A combination of oral decitabine 35 mg with oral cedazuridine 100 mg was established as the recommended phase 2 dose. Phase 2 data confirmed bioequivalence of C-DEC when compared with parenteral decitabine, and a larger phase 3 trial has demonstrated similar results, leading to the FDA approval of C-DEC for use in intermediate/high-risk myelodysplastic syndrome (MDS) and CMML. This review will focus upon the current role of HMA therapy in MDS/CMML, preclinical and clinical development of C-DEC, and potential roles of oral HMA therapy in myeloid malignancies moving forward.
Topics: Azacitidine; Decitabine; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Uridine
PubMed: 33904891
DOI: 10.1182/bloodadvances.2020002929 -
Blood Cancer Journal Dec 2022Venetoclax (VEN) combined with azacitidine (AZA) or decitabine (DEC) has been approved for older adults with acute myeloid leukemia (AML) unfit for intensive...
Venetoclax (VEN) combined with azacitidine (AZA) or decitabine (DEC) has been approved for older adults with acute myeloid leukemia (AML) unfit for intensive chemotherapy based on the pivotal VIALE-A trial. However, this trial only compared AZA + VEN with AZA monotherapy. Therefore, we compared the outcomes of consecutive older adults (65 years or older) with newly diagnosed AML who received DEC (n = 230) or DEC + VEN (n = 74) after propensity score matching to construct a one-to-one matched cohort by the nearest neighbor algorithm. The median overall survival was longer in the DEC + VEN group than in the DEC group (13.4 months vs. 8.3 months, p = 0.01). The median event-free survivals were 8.6 and 5.8 months in the DEC + VEN and DEC groups, respectively (p = 0.02). The response rate (complete response, complete response with incomplete hematologic recovery, and morphologic leukemia-free state) was significantly higher in the DEC + VEN group than in the DEC group (70.3% vs. 24.3%, p < 0.01). The 30-day (2.7% vs. 9.5%, p = 0.17) and 60-day (9.5% vs. 18.9%, p = 0.16) mortality rates did not differ between the two groups, nor did the median hospitalization and transfusion rates (hospitalization: 23 days vs. 21 days, p = 0.20; red blood cells: 3.2 units/month vs. 3.5 units/month, p = 0.73; platelets: 2.7 units/month vs. 2.3 units/months, p = 0.48). Of those who received DEC + VEN and became leukemia-free, 29% underwent allogeneic stem cell transplantation and had excellent survival outcomes (one-year survival: 79.4%; one-year non-relapse mortality: 13.3%). This study is the first to provide real-world evidence that DEC + VEN has superior outcomes to DEC monotherapy.
Topics: Humans; Aged; Decitabine; Propensity Score; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute; Azacitidine
PubMed: 36529771
DOI: 10.1038/s41408-022-00770-x -
Blood Feb 2013The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and...
The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?
Topics: Animals; Azacitidine; Decitabine; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute
PubMed: 23449614
DOI: 10.1182/blood-2013-02-483735 -
Future Oncology (London, England) Jun 2021Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant... (Review)
Review
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Decitabine; Disease Management; Drug Approval; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Treatment Outcome; Uridine
PubMed: 33709786
DOI: 10.2217/fon-2020-1210 -
The Journal of International Medical... Jul 2022Combination therapy has become the hallmark of lung cancer treatment, as it reduces the dosage intensity of individual drugs while increasing their efficacy. In the...
OBJECTIVE
Combination therapy has become the hallmark of lung cancer treatment, as it reduces the dosage intensity of individual drugs while increasing their efficacy. In the current study, we analyzed the combinatorial effect of decitabine and aspirin on non-small cell lung cancer (NSCLC) cell growth.
METHODS
In this study, we investigated the combinatorial effect of decitabine and aspirin by MTT, colony formation, and Transwell assays. We also explored the underlying molecular mechanism a series of and experiments.
RESULTS
The combination of decitabine and aspirin regulated cell viability and migration . Moreover, the combination therapy suppressed tumor cell growth by inhibiting the β-catenin/STAT3 signaling pathway. Our study also found that the regimen increased the phosphorylation of β-catenin and decreased the expression of STAT3 and β-catenin.
CONCLUSION
The combined administration of decitabine and aspirin significantly reduced tumor growth compared with single-agent treatment and the control . The study results indicated that decitabine and aspirin could suppress NSCLC cell growth and metastasis the β-catenin/STAT3 signaling pathway.
Topics: Aspirin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Decitabine; Humans; Lung Neoplasms; Wnt Signaling Pathway; beta Catenin
PubMed: 35869624
DOI: 10.1177/03000605221112024 -
Blood Dec 2022Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic fitness of MDSCs is fundamental for its...
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic fitness of MDSCs is fundamental for its suppressive activity toward effector T cells. Our previous studies showed that the number and inhibitory function of MDSCs were impaired in patients with immune thrombocytopenia (ITP) compared with healthy controls. In this study, we analyzed the effects of decitabine on MDSCs from patients with ITP, both in vitro and in vivo. We found that low-dose decitabine promoted the generation of MDSCs and enhanced their aerobic metabolism and immunosuppressive functions. Lower expression of liver kinase 1 (LKB1) was found in MDSCs from patients with ITP, which was corrected by decitabine therapy. LKB1 short hairpin RNA (shRNA) transfection effectively blocked the function of MDSCs and almost offset the enhanced effect of decitabine on impaired MDSCs. Subsequently, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP in murine models. Passive transfer of decitabine-modulated MDSCs significantly raised platelet counts compared with that of phosphate buffered saline-modulated MDSCs. However, when LKB1 shRNA-transfected MDSCs were transferred into SCID mice, the therapeutic effect of decitabine in alleviating thrombocytopenia was quenched. In conclusion, our study suggests that the impaired aerobic metabolism of MDSCs is involved in the pathogenesis of ITP, and the modulatory effect of decitabine on MDSC metabolism contributes to the improvement of its immunosuppressive function. This provides a possible mechanism for sustained remission elicited by low-dose decitabine in patients with ITP.
Topics: Animals; Mice; Purpura, Thrombocytopenic, Idiopathic; Myeloid-Derived Suppressor Cells; Decitabine; Mice, SCID; Thrombocytopenia; Liver
PubMed: 36037415
DOI: 10.1182/blood.2022016029