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Molecules (Basel, Switzerland) May 2021Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete.... (Review)
Review
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Topics: Acyclovir; Atenolol; Atovaquone; Catalysis; Chemistry, Pharmaceutical; Decitabine; Dopamine; Enzymes; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Molecular Conformation; Nucleosides; Phenylephrine; Prodrugs; Protons; Quantum Theory; Software; Technology, Pharmaceutical; Temperature; Tranexamic Acid
PubMed: 34071328
DOI: 10.3390/molecules26113248 -
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 -
NEJM Evidence Oct 2022Therapeutic options for myelodysplastic syndromes (MDS) are highly risk stratified, with more toxic treatments reserved for patients at higher risk and more supportive...
Therapeutic options for myelodysplastic syndromes (MDS) are highly risk stratified, with more toxic treatments reserved for patients at higher risk and more supportive approaches favored for those with lower-risk disease. The hypomethylating agents azacitidine (AZA) and decitabine (DEC) are recommended as first-line therapy for higher-risk MDS; for lower-risk disease, the focus is primarily on treating symptomatic anemia with hematopoietic growth factors, luspatercept, or lenalidomide.
Topics: Humans; Decitabine; Myelodysplastic Syndromes; Azacitidine; Lenalidomide; Anemia
PubMed: 38319862
DOI: 10.1056/EVIDe2200165 -
Blood Apr 2023Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and...
Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.
Topics: Humans; Decitabine; Ipilimumab; Myelodysplastic Syndromes; Azacitidine; Leukemia, Myeloid, Acute
PubMed: 36332187
DOI: 10.1182/blood.2022017686 -
Current Treatment Options in Oncology Oct 2018Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the... (Review)
Review
Aging is the most potent of carcinogens, especially for the bone marrow stem cell clonal disorders called myelodysplastic syndromes (MDS). Age-associated changes in the microenvironment or the soil of the bone marrow (BM) as well as in the cell or the seed provide a growth advantage for clonal myeloid cells. Slowly accumulating senescent cells which can no longer divide because they have reached the end of their proliferative life cycle, but which continue to produce metabolic debris, overwhelm the natural autophagy mechanisms resulting in pro-inflammatory changes in the BM soil. In addition, the seed or stem cells acquire passenger mutations with each round of proliferation resulting from DNA copying errors. Some mutations commonly associated with MDS can be found in older, otherwise healthy individuals; however, when combined with other passenger mutations or in the setting of a noxious soil, the result could be a proliferative advantage for one stem cell over others, leading to its clonal expansion and development of the clinical syndrome. When considering therapeutic options for MDS patients, the important considerations are related to both the common co-morbidities of an elderly population along with the heterogeneous passenger mutations and the inflammatory changes in the soil. At present, allogeneic stem cell transplant is the only potentially curative option in MDS. Palliative strategies are directed at improving the quality of life and prolonging survival. Only three drugs are FDA approved, two being the hypomethylating agents azacytidine and decitabine while the third is lenalidomide which is restricted to lower risk MDS patients with deletion 5q. Promising future therapies are directed at reversing the pro-inflammatory changes in the microenvironment (luspatercept) or targeting specific mutations isocitrate dehydrogenase (IDH)1, IDH2, p53, EZH2. More durable responses are to be expected when the seed and soil are targeted simultaneously through a combination of drugs.
Topics: Aging; Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Enzyme Inhibitors; Humans; Lenalidomide; Myelodysplastic Syndromes; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 30362079
DOI: 10.1007/s11864-018-0583-4 -
Cell Reports Sep 2023Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using...
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.
Topics: Humans; Decitabine; Azacitidine; Antimetabolites, Antineoplastic; Leukemia, Myeloid, Acute; DNA Methylation; DNA; Adaptor Proteins, Signal Transducing
PubMed: 37714156
DOI: 10.1016/j.celrep.2023.113098 -
Advanced Science (Weinheim,... May 2023The regulation of tumor immunosuppressive microenvironments via precise drug delivery is a promising strategy for preventing tumor recurrence and metastasis. Inspired by...
The regulation of tumor immunosuppressive microenvironments via precise drug delivery is a promising strategy for preventing tumor recurrence and metastasis. Inspired by the stealth strategy, a stealthy nanovehicle based on neutrophil camouflage is developed to achieve precise delivery and tumor immunotherapy by triggering pyroptosis. The nanovehicle comprises anti-CD11b- and IR820-conjugated bovine serum albumin nanoparticles loaded with decitabine. Camouflaged by neutrophils, the nanovehicles achieve efficient tumor delivery by neutrophil hitchhiking owing to the biotropism of neutrophils for tumors. The fluorescent signal molecule, IR820, on the nanovehicle acts as a navigation monitor to track the precise delivery of the nanovehicle. The released decitabine upregulates gasdermin E, and laser irradiation activates caspase-3, thereby resulting in pyroptosis, which improves the system's adaptive immune response. In a triple-negative breast cancer animal model, it regulates the immunosuppressive microenvironment for effective tumor immunotherapy and induces a long-lasting and strong immune memory to prevent lung metastasis.
Topics: Animals; Pyroptosis; Neutrophils; Decitabine; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 36967574
DOI: 10.1002/advs.202207456 -
Expert Review of Hematology May 2018The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of... (Review)
Review
The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes. A literature search was performed using PubMed to find recent major publications, which provide biological and clinical research about epigenetic therapy in AML patients. Expert commentary: Numerous studies have demonstrated that HMA therapy with AZA or DAC may lead to significant response rates, even in pre-treated patients. Nevertheless, there is still an unmet need to further improve outcome in elderly AML patients. Therefore, novel treatment combinations are needed and some of them, such as AZA plus venetoclax, already show promising results.
Topics: Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 29543073
DOI: 10.1080/17474086.2018.1453802 -
Biochimica Et Biophysica Acta. Reviews... Mar 2024Decitabine's early successful therapeutic outcomes in hematologic malignancies have led to regulatory approvals from the Food and Drug Administration (FDA) and the... (Review)
Review
Decitabine's early successful therapeutic outcomes in hematologic malignancies have led to regulatory approvals from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for addressing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These approvals have sparked keen interest in exploring the potential of decitabine for treating solid tumors. Continuous preclinical and clinical trials have proved that low doses of decitabine also bring benefits in treating solid tumors, and various proposed mechanisms attempt to explain the potential efficacy. It is important to note that the application of decitabine in solid tumors is still considered investigational. This article reviews the application mechanism and current status of decitabine in the treatment of solid tumors.
Topics: United States; Humans; Decitabine; Azacitidine; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Epigenesis, Genetic
PubMed: 38163523
DOI: 10.1016/j.bbcan.2023.189066 -
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