Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BCR-ABL1 inhibitors decrease cholesterol and atherosclerosis, and activate coagulation in a translational mouse model

ABSTRACT: Objectives: Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the multifactorial process of TKI-induced vascular adverse effects in a translational model for atherosclerosis, the APOE3*Leiden.CETP mouse. Approach and results: Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed throughout the study, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, :<0.001; ponatinib 3mg/kg, -37%, P<0.001; ponatinib 10 mg/kg -44%, P<0.001) and atherosclerotic lesion area (imatinib, -78%, P<0.001; ponatinib 3 mg/kg, -52%, P=0.014; ponatinib 10 mg/kg, -48%, P=0.001), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis predicted that ponatinib may lead to a pro-coagulant state by adversely affecting coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. The coagulation factor VII in plasma was increased by ponatinib, whereas nilotinib increased FVIIa. Conclusion: Imatinib showed a beneficial cardiovascular risk profile, whereas nilotinib and ponatinib increase the cardiovascular risk through induction of a pro-thrombotic state.

ORGANISM(S): Mus musculus

PROVIDER: GSE103908 | GEO | 2018/05/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

PAD4 Inhibition is Sufficient for the Amelioration of Collagen-Induced Arthritis

Project description:To examine the effects of GSK199 treatment on antibody responses, a synovial antigen array analysis was performed using day 35 sera derived from mice with CIA treated with 30 mg/kg qd, 30 mg/kg bid GSK199 or saline. The synovial antigen arrays contain nearly 200 peptides and proteins, both citrullinated and uncitrullinated, representing candidate antigens in RA. Significance Analysis of Microarrays identified 7 and 14 autoantibody reactivities that were statistically decreased in CIA mice treated with 30 mg/kg qd or 30 mg/kg bid GSK199 respectively, compared to PBS treatment. By comparison, over 150 native and citrullinated epitopes on the arrays did not exhibit significant differences in reactivity. Sera from mice treated with 30 mg/kg GSK199 qd exhibited decreased IgG reactivity to native epitopes such as peptides from human fibrinogen alpha and beta chains and keratin while sera from mice treated with 30 mg/kg bid GSK199 demonstrated decreased IgG reactivity to native epitopes including collagen IV, heat shock protein 65, peptides from human fibrinogen alpha and beta chains (two of which match those that were decreased in the 30 mg/kg qd group), and vimentin as compared to saline controls (q < 0.1%). Decreased autoantibody reactivity to citrullinated peptides from vimentin and fibromodulin were also observed in sera from mice treated with 30 mg/kg bid GSK199 compared to controls treated with saline (q < 0.1%), but not by GSK199 30 mg/kg qd. There were no differences between treatment with GSK199 or saline alone in the levels of autoantibodies to 38 other citrullinated proteins in the array. These data demonstrated that GSK199 treatment decreases the development of autoantibodies in CIA and impairs epitope spreading to a degree similar to that observed with pan-PAD inhibition.

2015-10-08 | GSE69680 | GEO

Therapeutic efficacy of INX-315, a selective CDK2 inhibitor, in solid tumors [OV5398PDX RNAseq]

Project description:We performed RNA sequencing on tumors harvested from OV5398 (ovarian) PDX treated for 40-50 days with either control vehicle (PEG), 100 mg/kg BID INX-315 or 200 mg/kg QD INX315.

2023-11-22 | GSE243151 | GEO

Gene expression profiling of KU812 CD25 shRNA vs KU812 control random shRNA

Project description:In chronic myeloid leukemia (CML) neoplastic stem cells (NCS) represent a critical target of therapy. However, little is known about markers and targets expressed in CML NSC. We examined the phenotype and function of CD34+/CD38─/Lin─ CML LSC by a multi-parameter screen approach employing antibody-phenotyping, mRNA expression profiling, and functional studies, followed by marker-validation using diverse control-cohorts and follow-up samples of CML patients treated with imatinib. We here show that in contrast to normal stem cells, CD34+/CD38− CML NSC express IL2RA (CD25), and that STAT5 induces expression of CD25 in Lin−/Sca-1+/Kit+ NSC (LSK) in C57/Bl6 mice. Correspondingly, expression of CD25 decreased in the human BCR/ABL1+ stem cell line KU812 upon shRNA-induced STAT5-depletion. The BCR/ABL1-inhibitors nilotinib and ponatinib were also found to decrease STAT5 activity and CD25-expression in KU812 cells and primary CML NSC. A CD25-targeting shRNA augmented the proliferation of KU812 cells in vitro and in vivo in NOD/SCID-IL2R-/- mice. In consecutive experiments the PI3K/mTOR-blocker BEZ235 was found to promote STAT5- and CD25 expression and to produce synergistic anti-neoplastic effects with nilotinib and ponatinib in CML cells. Together, CD25 is a novel STAT5-dependent marker and target in CML NSC.

2016-01-26 | GSE60315 | GEO

Methylation data from biological replicates of imatinib and nilotinib resistant K-562 cells

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.1 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We analyzed genome-wide methylation to investigate changes in methylation during the development of TKI resistance.

2022-05-21 | GSE203443 | GEO

Gene expression data from biological replicates of imatinib and nilotinib resistant K-562 cells

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.1 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We performed microarrays to analyze the changes in gene expression during the development of TKI resistance.

2022-05-21 | GSE203442 | GEO

Gene expression data from biological replicates of imatinib and nilotinib resistant K-562 cells.

Project description:Resistant cells were generated by stepwise exposure to increasing concentrations of imatinib or nilotinib to establish 0.5 and 2 µM imatinib and 0.05 µM nilotinib resistant cells. This procedure was performed twice independently to establish biological replicates of TKI resistance. We performed microarrays (Clariom S) to analyze the changes in gene expression during the development of TKI resistance.

2023-06-30 | GSE227347 | GEO

Transcription profiling of human K562 cells reveals Imatinib and Nilotinib induced molecular changes in Philadelphia chromosome-positive Chronic Myelogenous Leukemia

Project description:Chronic myelogenous leukemia (CML) is a malignant stem cell disease characterized by a reciprocal translocation between chromosome 9 and 22. The selective bcr-abl tyrosine-kinase inhibitor Imatinib has become the therapy of choice for patients with newly diagnosed CML including those previously considered candidates for allogeneic haematopoietic stem cell transplantation. The tyrosine-kinase inhibitor Nilotinib is a derivate of Imatinib with higher potency. To examine the molecular and functional effects of Nilotinib and Imatinib in chronic myelogenous leukemia, we performed gene expression and functional analyses in K562 cells following treatment with the two tyrosine kinase inhibitors. Experiment Overall Design: Affymetrix U133A 2.0 microarrays were used to examine the gene expression profile of K562 cells after in vitro treatment with Imatinib (0.5 ÂµM) or Nilotinib (0.05 ÂµM) for 24 hours. Gene expression data of the treated cells were compared with data of untreated cells.

2010-01-19 | E-GEOD-19567 | biostudies-arrayexpress

Transcriptional profiling of the Candida auris response to exogenous farnesol exposure

Project description:The antifungal resistance threat posed by Candida auris necessitates bold and innovative therapeutic options. Farnesol, a quorum-sensing molecule with a potential antifungal and/or adjuvant effect; it may be a promising candidate in alternative treatment regimens. To gain further insights into the farnesol-related effect on C. auris, genome-wide gene expression analysis was performed using RNA-Seq. Farnesol exposure resulted in 1,766 differentially expressed genes. Of these, 447 and 304 genes with at least 1.5-fold increase or decrease in expression, respectively, were selected for further investigation. Genes involved in morphogenesis, biofilm events (maturation and dispersion), gluconeogenesis, iron metabolism, and regulation of RNA biosynthesis showed down-regulation, whereas those related to antioxidative defense, transmembrane transport, glyoxylate cycle, fatty acid β-oxidation, and peroxisome processes were up-regulated. In addition, farnesol treatment increased the expression of certain efflux pump genes, including MDR1, CDR1, and CDR2. Growth, measured by change in CFU number, was significantly inhibited within 2 hours of the addition of farnesol (5.8×10^7±1.1×10^7 and 1.1×10^7±0.3×10^7 CFU/ml for untreated control and farnesol-exposed cells, respectively) (p<0.001). In addition, farnesol treatment caused a significant reduction in intracellular iron (152.2±21.1 vs. 116.0±10.0 mg/kg), manganese (67.9±5.1 vs. 18.6±1.8 mg/kg), and zinc (787.8±22.2 vs. 245.8±34.4 mg/kg) (p<0.05–0.001) compared to untreated control cells, whereas the level of cooper was significantly increased (274.6±15.7 vs. 828.8±106.4 mg/kg) (p<0.001). Our data demonstrate that farnesol significantly influences the growth, intracellular metal ion contents, and gene expression related to fatty acid metabolism, which could open new directions in developing alternative therapies against C. auris.

2021-09-30 | GSE180093 | GEO

Imatinib and Nilotinib induced molecular changes in Philadelphia chromosome-positive Chronic Myelogenous Leukemia

2009-12-19 | GSE19567 | GEO

INCREASED HEAT SHOCK PROTEIN 70 EXPRESSION BY CM-695 ASSOCIATES WITH STRONG ANTITROMBOTIC EFFECT WITHOUT INCREASING BLEEDING

Project description:BACKGROUND Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. We described that the heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. OBJECTIVES By using murine models, we want to test the hypothesis that overexpressing Hsp70 with CM-695, a dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. METHODS CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. RESULTS Intraperitoneal (i.p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [P=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs. 39.0 minutes (min) in the control group (CG), P=0.008, n≥10] and ferric chloride (OT: 14.7 vs. 9.2 min in the CG, P=0.032, n≥10) models. I.p. 80 mg/kg CM-695 (n≥9) and intravenous 3 mg/kg rivaroxaban (n≥8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs. 7.5 min in the CG, n≥10]. However, this was dramatically increased by rivaroxaban (BT: 30.0 vs. 13.7 min in the CG, P=0.001, n=10). CONCLUSIONS CM-695 is a new antithrombotic drug devoid of bleeding risk that may be envisioned as a useful clinical tool.

2020-01-13 | GSE93958 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data