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Suhrid Banskota, Sadan Dahal, Eunju Kwon, Dong Young Kim, Jung-Ae Kim
PURPOSE: Over half of the colon cancer patients suffer from cancer-related events, mainly metastasis. Loss of β-catenin activity has previously been found to facilitate cancer cell dissociation and migration. Here, we aimed to investigate whether epigenetic silencing of β-catenin induces human colon cancer cell migration and/or invasion. METHODS: HCT-116, Caco-2, HT-29 and SW620 cell migration and invasion capacities were assessed using scratch wound healing and Matrigel invasion assays, respectively...
June 19, 2018: Cellular Oncology (Dordrecht)
Zhan Wang, Zenan Wang, Shu Li, Binghao Li, Lingling Sun, Hengyuan Li, Peng Lin, Shengdong Wang, Wangsiyuan Teng, Xingzhi Zhou, Zhaoming Ye
γδ T cell-based immunotherapy for osteosarcoma (OS) has shown limited success thus far. DNA-demethylating agents not only induce tumor cell death but also have an immunomodulatory function. In this study, we have assessed the potential benefit of combining decitabine (DAC, a DNA demethylation drug) and γδ T cells for OS immunotherapy. DAC increased the expression of natural killer group 2D (NKG2D) ligands (NKG2DLs), including major histocompatibility complex class I-related chains B (MICB) and UL16-binding protein 1 (ULBP1), on the OS cell surface, making the cells more sensitive to recognition and destruction by cytotoxic γδ T cells...
2018: Frontiers in Immunology
Tianwei Lin, Shaokang Dang, Qian Su, Huiping Zhang, Junli Zhang, Lin Zhang, Xiaoxiao Zhang, Yong Lu, Hui Li, Zhongliang Zhu
An increasing number of epidemiological investigations and animal models research suggest that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the promoter methylation of metabotropic glutamate receptor 1 (mGluR1) and metabotropic Glutamate Receptor 5 (mGluR5) gene modification on PS induced depression-like behavior in offspring rats (OR). PS models were established, with or without 5-aza-2′-deoxycytidine (5-azaD, decitabine) treatment...
May 23, 2018: Journal of Clinical Medicine
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years). DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations...
June 2018: American Journal of Hematology
Shigeru Chiba
Azacitidine (AZA), a hypomethylating agent, is widely used in patients with high-risk (HR) myelodysplastic syndromes (MDS). AZA is also believed to aid in the treatment of acute myeloid leukemia (AML). In randomized clinical trials for MDS, major and overall response rates for AZA alone were 16-33% and 38-60%, respectively. In the AZA-001 trial, the median overall survival (OS) for the AZA group was >24 months compared to 15 months for the control. However, other clinical trials have reported OS periods of 15-21 months, while population-based studies have reported OS rates much shorter than 20 months...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Peng Liu, Liwei Zhao, Friedemann Loos, Kristina Iribarren, Oliver Kepp, Guido Kroemer
A systematic search for anticancer agents that may induce the release of high mobility group box 1 (HMGB1) protein from cells into the extracellular space has led to the identification of several drugs capable of elevating plasma HMGB1 levels in vivo , in mice. Such agents include bona-fide immunogenic cell death inducers such as oxaliplatin, as well as a series of epigenetic modifiers, namely azacitidine, decitabine, and suberoylanilide hydroxamic acid (SAHA).
2018: Oncoimmunology
Sharon McGrath-Morrow, Roland Ndeh, Kathryn A Helmin, Shang-Yang Chen, Kishore R Anekalla, Hiam Abdala-Valencia, Franco R D'Alessio, J Michael Collaco, Benjamin D Singer
Pediatric acute lung injury, usually due to pneumonia, has a mortality rate of more than 20% and an incidence that rivals that of all childhood cancers combined. CD4+ T-cells coordinate the immune response to pneumonia but fail to function robustly among the very young, which have poor outcomes from lung infection. We hypothesized that DNA methylation represses a mature CD4+ T-cell transcriptional program in neonates with pneumonia. Here, we found that neonatal mice (3-4 days old) aspirated with Escherichia coli bacteria had a higher mortality rate than juvenile mice (11-14 days old)...
June 4, 2018: Journal of Biological Chemistry
Hoda Kardooni, Estela Gonzalez-Gualda, Emmanouil Stylianakis, Sina Saffaran, Jonathan Waxman, Robert M Kypta
The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity...
May 28, 2018: Cancers
Cheng-Wei Li, Tzu-Ying Lai, Bor-Sen Chen
Mutation accumulation and epigenetic alterations in genes are important for carcinogenesis. Because leukemogenesis-related signal pathways have been investigated and microarray sample data have been produced in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and normal cells, systems analysis in coupling pathways becomes possible. Based on system modeling and identification, we could construct the coupling pathways and their associated gene regulatory networks using microarray sample data. By applying system theory to the estimated system model in coupling pathways, we can then obtain transductivity sensitivity, basal sensitivity and error sensitivity of each protein to identify the potential impact of genetic mutations, epigenetic alterations and the coupling of other pathways from the perspective of energy, respectively...
May 4, 2018: Oncotarget
David P Steensma
Myelodysplastic syndromes (MDS) include a group of clonal myeloid neoplasms characterized by cytopenias due to ineffective hematopoiesis, abnormal blood and marrow cell morphology, and a risk of clonal evolution and progression to acute myeloid leukemia (AML). Because outcomes for patients with MDS are heterogeneous, individual risk stratification using tools such as the revised International Prognostic Scoring System (IPSS-R) is important in managing patients-including selecting candidates for allogeneic hematopoietic stem cell transplantation (ASCT), the only potentially curative therapy for MDS...
May 24, 2018: Blood Cancer Journal
Anne Sophie Kubasch, Uwe Platzbecker
Higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) of the elderly exhibit several commonalities, including first line treatment with hypomethylating agents (HMA) like azacitidine (AZA) or decitabine (DAC). Until today, response to treatment occurs in less than 50 percent of patients, and is often short-lived. Moreover, patients failing HMA have a dismal prognosis. Current developments include combinations of HMA with novel drugs targeting epigenetic or immunomodulatory pathways. Other efforts focus on the prevention of resistance to HMA using checkpoint inhibitors to enhance immune attack...
May 24, 2018: Cancers
W Y Li, Y F Feng, X Ma, H Y Qiu, C C Fu, X W Tang, Y Han, D P Wu, A N Sun
Objective: To probe the feasibility of decitabine (DAC) combined with micro-transplantation as consolidation treatment for older patients with acute myeloid leukemia (AML). Methods: Between November 2012 and September 2015, 37 consecutive patients with AML ≥60 years of age were analyzed. Of them, 19 patients received consolidation therapy with DAC followed by micro-transplantation (microtransplant group). Another 18 ones (chemo group) were treated with DAC plus priming regimen as consolidation chemotherapy in the same period...
April 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Tao Jiang, Fujue Wang, Lianjie Hu, Xiaomin Cheng, Yuhuan Zheng, Ting Liu, Yongqian Jia
[This corrects the article DOI: 10.18632/oncotarget.20659.].
April 20, 2018: Oncotarget
Siddhesh Arun Kalantri, Rudra Ray, Arnab Chattopadhyay, Sunistha Bhattacharjee, Ankita Biswas, Maitreyee Bhattacharyya
To study safety, efficacy (hemoglobin and hemoglobin F percentage increment in non-transfusion-dependent patients and decrease in transfusion frequency in transfusion-dependent patients), and determinants of response of decitabine in patients with HbE/β-thalassemia. Thirty patients of HbE/β-thalassemia (age > 18 years) were enrolled. Both transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) patients were included after obtaining informed consent. Participants received 0.2 mg/kg of 5-aza-2'-deoxycytidine (decitabine) subcutaneously on 2 consecutive days a week for at least 12 weeks...
May 9, 2018: Annals of Hematology
Huan Liu, Juan Cheng, Long Zhao, Qian Xu, Mingming Xue, Shuling Zhang, Bei Liu
The present study describes a patient with high-risk chronic myelomonocytic leukemia (CMML), for whom decitabine therapy achieved partial remission, prior to a sudden transformation to acute myeloid leukemia (AML) and an inferior outcome. The 53-year-old male reported easily bruising for 5 months. Examination indicated a diagnosis of CMML. Chromosome analysis identified a 48, XY, +8, +21 karyotype, classifying the patient as high-risk, according to a clinical/molecular CPSS (CPSS-Mol) model. Gene sequencing detected a mutation in DNA methyltransferase 3α, which is relatively rarely identified in CMML and has recently been reported to have an independent prognostic impact on overall survival time...
May 2018: Oncology Letters
Matthieu Duchmann, Fevzi F Yalniz, Alessandro Sanna, David Sallman, Catherine C Coombs, Aline Renneville, Olivier Kosmider, Thorsten Braun, Uwe Platzbecker, Lise Willems, Lionel Adès, Michaela Fontenay, Raajit Rampal, Eric Padron, Nathalie Droin, Claude Preudhomme, Valeria Santini, Mrinal M Patnaik, Pierre Fenaux, Eric Solary, Raphael Itzykson
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing...
April 25, 2018: EBioMedicine
C Roolf, A Richter, C Konkolefski, G Knuebel, A Sekora, S Krohn, J Stenzel, B J Krause, B Vollmar, H Murua Escobar, C Junghanss
BACKGROUND: Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias. METHODS: Here, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL...
May 4, 2018: Journal of Hematology & Oncology
Gail J Roboz, Ellen K Ritchie, Yulia Dault, Linda Lam, Danielle C Marshall, Nicole M Cruz, Hsiao-Ting C Hsu, Duane C Hassane, Paul J Christos, Cindy Ippoliti, Joseph M Scandura, Monica L Guzman
Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m2 days 1-10 and escalating doses of plerixafor (320-810 mcg/kg) days 1-5. Sixty-nine patients were treated, with overall response rate 43%...
May 3, 2018: Haematologica
Jia Yu, Bo Qin, Ann M Moyer, Somaira Nowsheen, Tongzheng Liu, Sisi Qin, Yongxian Zhuang, Duan Liu, Shijia W Lu, Krishna R Kalari, Daniel W Visscher, John A Copland, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Donald W Northfelt, Richard J Gray, Zhenkun Lou, Vera J Suman, Richard Weinshilboum, Judy C Boughey, Matthew P Goetz, Liewei Wang
Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response...
June 1, 2018: Journal of Clinical Investigation
Richard Daifuku, Sheila Grimes, Murray Stackhouse
5-aza-2′,2′-difluorodeoxycytidine (NUC013) has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013. NUC013 was conjugated with trimethylsilanol (TMS) at the 3′ and 5′ position of the sugar, rendering the molecule hydrophobic and producing 3′,5′-di-trimethylsilyl-2′,2′-difluoro-5-azadeoxycytidine (NUC041)...
April 23, 2018: Pharmaceuticals
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