DNA Methylation–Targeted Drugs

Costa, Elodie M. Da; McInnes, Gabrielle; Beaudry, Annie; Raynal, Noël J.-M.

doi:10.1097/ppo.0000000000000278

Cited by 30 publications

(22 citation statements)

References 81 publications

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“…However, the high cost, easy relapse, severe GVHD side effects and technical limitations make hematopoietic stem cell transplantation hard to carry out for most leukemia patients in China (27). In recent years, the research and development of targeted drugs has become a hot spot (28,29). The prognosis of many hematological malignancies has greatly improved because of the new drugs (30).…”

Section: Discussionmentioning

confidence: 99%

3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression

et al. 2019

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Three dimensional (3D) culture has gradually become a research hotspot in the field of drug screening, stem cell research, and tissue engineering due to its more physiological-like morphology and function. In this study, we compared the differences of cell proliferation, population, protein expression and chemoresistance profiles between two dimensional (2D) and 3D culture of acute lymphoblastic leukemia (ALL) Jurkat cell line. Polycaprolactone (PCL) is used for 3D culture owing to its biochemical properties and compatibility. Culturing of ALL Jurkat cell line in collagen type I coated polycaprolactone scaffold for 168 h increased cell proliferation, attachment, as well as the drug resistance to cytarabine (Ara-C) and daunorubicin (DNR) without changing the original CD2+CD3+CD4+dimCD8−CD34−CD45+dim phenotype, compared to uncoated PCL scaffold and tissue culture plate systems. Molecularly, increased chemoresistance is associated with the upregulation of discoidin domain receptor 1 (DDR1) and transcription factor STAT3. Inhibition of DDR1 activity by DDR1-specific inhibitor DDR-IN-1 accelerated cell death in the presence of Ara-C, DNR or their combination. These results demonstrated that 3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression. Importantly, the cell adhesion-mediated drug resistance induced by DDR1 in the scaffold was similar to the clinical situation, indicating the 3D culture of cancer cells recapitulate the in vivo tumor environment and this platform can be used as a promising pre-clinic drug-screen system.

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Section: Discussionmentioning

confidence: 99%

3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression

et al. 2019

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“…Indeed, DNA methylation biomarkers with diagnostic, prognostic, and predictive power are already in clinical trials or in a clinical setting [60]. DNA methyltransferase inhibitors have been approved for the treatment of several hematopoietic malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia (AML) [61]. Other epigenetic regulatory mechanisms also play a critical role in the pathogenesis of AML.…”

Section: Epigenetics In Disease Contextmentioning

confidence: 99%

From Genotype to Phenotype: Through Chromatin

Romanowska

Joshi

2019

Genes

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Advances in sequencing technologies have enabled the exploration of the genetic basis for several clinical disorders by allowing identification of causal mutations in rare genetic diseases. Sequencing technology has also facilitated genome-wide association studies to gather single nucleotide polymorphisms in common diseases including cancer and diabetes. Sequencing has therefore become common in the clinic for both prognostics and diagnostics. The success in follow-up steps, i.e., mapping mutations to causal genes and therapeutic targets to further the development of novel therapies, has nevertheless been very limited. This is because most mutations associated with diseases lie in inter-genic regions including the so-called regulatory genome. Additionally, no genetic causes are apparent for many diseases including neurodegenerative disorders. A complementary approach is therefore gaining interest, namely to focus on epigenetic control of the disease to generate more complete functional genomic maps. To this end, several recent studies have generated large-scale epigenetic datasets in a disease context to form a link between genotype and phenotype. We focus DNA methylation and important histone marks, where recent advances have been made thanks to technology improvements, cost effectiveness, and large meta-scale epigenome consortia efforts. We summarize recent studies unravelling the mechanistic understanding of epigenetic processes in disease development and progression. Moreover, we show how methodology advancements enable causal relationships to be established, and we pinpoint the most important issues to be addressed by future research.

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“…However, the antineoplastic activity of HMAs azacitidine (AZA) and decitabine (DEC) in all patients with AML and MDS (regardless of mutational status) is clear. 33 The exact mechanism of action of these HMAs is unclear, but the antileukemic effects are thought to be secondary to degradation of DNMTs that lead to global DNA hypomethylation, gene reactivation, DNA damage, and eventual cell death. 34 AZA and DEC are US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for the treatment of MDS, chronic myelomonocytic leukemia (CMML), and AML, with slight variations in specific approvals in Europe and the United States.…”

Section: Dna Methylation: Targeting Dna Methyltransferases Tet and mentioning

confidence: 99%

Insights into novel emerging epigenetic drugs in myeloid malignancies

Chandhok

Prébet

2019

Therapeutic Advances in Hematology

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Epigenetics has been defined as ‘a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence’ and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators.

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DNA Methylation–Targeted Drugs

Cited by 30 publications

References 81 publications

3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression

3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression

From Genotype to Phenotype: Through Chromatin

Insights into novel emerging epigenetic drugs in myeloid malignancies

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