Skip to content

Structures and Small Molecule Inhibitors in Cellular and Animal Models

My WordPress Blog

Menu
  • Sample Page
Menu

4 Combined treatment with chidamide and MI-3 disrupts DNA damage response

Posted on May 29, 2023 by president2010

4 Combined treatment with chidamide and MI-3 disrupts DNA damage response. expressed in MOLM-13 cells treated with MI-3 vs. ITGA6 chidamide alone or Picaridin in combination. Physique S6. Treatment with chidamide results in increased acetylation of Picaridin histone H3 in both MLL-r and non-MLL-r AML cells. (DOCX 3896 kb) 13148_2019_723_MOESM1_ESM.docx (3.8M) GUID:?57F59A1C-9635-4558-9D15-DE1D6D337F6D Additional file 2: Table S1. List of all genes that were differentially expressed in cells exposed to MI-3, chidamide, or both, in which 635 overlapped genes shown in the Venn Diagram (Physique 3C) as well as 59 genes indicated by a square (Physique 3D) are highlighted in pink and yellow, respectively. (XLSX 1820 kb) 13148_2019_723_MOESM2_ESM.xlsx (1.8M) GUID:?D625CED2-C137-4A5F-BDA1-AA48E79A6804 Data Availability StatementThe RNAseq datasets of the present study are available on request from your corresponding author. Abstract While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein conversation have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL conversation target the transcription-regulatory machinery involving Picaridin epigenetic regulation Picaridin of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of brokers might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that this combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL conversation inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to strong apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not nonhomologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-B) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL conversation inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia. Electronic supplementary material The online version of this article (10.1186/s13148-019-0723-0) contains supplementary material, which is available to authorized users. 0.05, ** 0.01, and *** 0.001 for comparison with each single agent. c, d MOLM-13 (c) and MV4-11 (d) cells were treated as explained in Additional file 2: Supplemental Table 1, followed by the analysis of Picaridin cell viability as above, after which the CompuSyn analysis was performed to determine whether the conversation between these two brokers is usually synergistic (CI value 1.0) Co-exposure to chidamide and MI-3 induces apoptosis of MLL-rearrangement AML cells, in association with increased ROS generation and mitochondrial injury To validate the synergistic effect of the regimen combining chidamide and MI-3 on MLL-r AML cells, the colony formation assay was performed. As shown in Fig. ?Fig.2a,2a, whereas chidamide (2.6 M) and MI-3 (13.9 M) displayed moderate single-agent activity, a significant reduction in colony formation was observed in MOLM-13 cells after combined treatment, compared with these two brokers alone. Analogous results were obtained from MV4-11, another MLL-r AML cells (Additional file 1: Physique S3A). Moreover, circulation cytometry with Annexin V/PI staining was then performed to examine whether chidamide would interact with MI-3 to induce apoptosis in MLL-r cells. After exposing to chidamide and MI-3 alone or in combination for 48 h, the percentage of apoptotic (Annexin V-positive) cells was significantly increased in MOLM-13 (Fig. ?(Fig.2b)2b) and MV4-11 cells (Additional file 1: Physique S3B), compared to each single agent. As loss of mitochondrial membrane potential (MMP) plays a crucial role in the initiation of intrinsic mitochondrion-dependent apoptotic cascade [25], we next examined the effect of chidamide and MI-3 individually or in combination on MMP. Consistent with the results for apoptosis, combined treatment with chidamide and MI-3 also induced loss of MMP, reflected by impaired mitochondrial depolarization indicated by markedly decreased fluorescence intensity ratio between JC-1 aggregate and monomer (Fig. ?(Fig.2c2c and Additional file 1: Physique S3C). To unveil the potential mechanism underlying the synergistic conversation between these two brokers in the induction of apoptosis, circulation cytometry was carried out to monitor intracellular ROS levels. After co-treated with chidamide and MI-3 for 48 h, a significant.

Recent Posts

  • To validate the grade of the computational modeling from the organic structures using the CDR variations, we assessed the modeled organic structures with regards to the effects of modeling uncertainties towards the results from the statistical analyses shown in Supplementary Fig
  • Change from baseline of visual functioning subscale in the thyroid-associated ophthalmopathy-specific quality of life level (GO-QOL)
  • Perhaps fine-tuned and targeted manipulations of nuclear receptor binding sites within promoters, enhancers and switch sites of the immunoglobulin loci will ultimately prove successful for the control and optimization of immunoglobulin expression
  • However, it really is worthwhile to remark that (a) the speed of MDR attacks in our people was considerably less than the main one reported in these research which (b) since only one 1 away of 3 situations of MDR-related septic shock was ICU-acquired, it’s possible which the administration of ivIgGAM in sufferers already admitted towards the ICU avoided their colonization and subsequent infection with these bacteria
  • To get this hypothesis, ibrutinib effectively reduced serum IgM at six months in every cases with clonal IgM (median reduction, 27% [IQR, 9%-39%];P=

Recent Comments

  1. A WordPress Commenter on Hello world!

Archives

  • May 2025
  • April 2025
  • March 2025
  • February 2025
  • January 2025
  • December 2024
  • November 2024
  • October 2024
  • September 2024
  • May 2023
  • April 2023
  • March 2023
  • February 2023
  • January 2023
  • December 2022
  • November 2022
  • October 2022
  • September 2022
  • August 2022
  • July 2022
  • June 2022
  • May 2022
  • April 2022
  • March 2022
  • February 2022
  • January 2022
  • December 2021
  • November 2021
  • October 2021
  • September 2021

Categories

  • Acetylcholine ??7 Nicotinic Receptors
  • Acetylcholine Nicotinic Receptors
  • Acyltransferases
  • Alpha1 Adrenergic Receptors
  • Angiotensin Receptors, Non-Selective
  • APJ Receptor
  • Calcium Channels
  • Carrier Protein
  • cMET
  • COX
  • DAT
  • Decarboxylases
  • Dipeptidyl Peptidase IV
  • DP Receptors
  • FFA1 Receptors
  • GlyR
  • H1 Receptors
  • HDACs
  • Hsp90
  • IGF Receptors
  • LXR-like Receptors
  • Miscellaneous Glutamate
  • Neurokinin Receptors
  • Nicotinic Acid Receptors
  • Nitric Oxide, Other
  • NO Synthase, Non-Selective
  • Non-selective Adenosine
  • Nucleoside Transporters
  • Opioid, ??-
  • Oxidative Phosphorylation
  • p70 S6K
  • PI 3-Kinase
  • Platelet-Activating Factor (PAF) Receptors
  • Potassium (KV) Channels
  • Potassium Channels, Non-selective
  • Prostanoid Receptors
  • Protein Ser/Thr Phosphatases
  • PTP
  • Retinoid X Receptors
  • Serotonin (5-ht1E) Receptors
  • Shp2
  • Sigma1 Receptors
  • Signal Transducers and Activators of Transcription
  • Sirtuin
  • Syk Kinase
  • T-Type Calcium Channels
  • Ubiquitin E3 Ligases
  • Ubiquitin/Proteasome System
  • Uncategorized
  • Urotensin-II Receptor
  • Vesicular Monoamine Transporters
© 2025 Structures and Small Molecule Inhibitors in Cellular and Animal Models | Powered by Minimalist Blog WordPress Theme