FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2980032444> ?p ?o ?g. }

• W2980032444 abstract "Abstract Abstract 3311 Bcl-2 family proteins are key regulators of apoptosis. Aberrations in Bcl2 levels are known to promote tumorigenesis and chemoresistance. Thus strategies to target Bcl2 will likely provide effective therapies for malignancies such as acute myeloid leukemia (AML). ABT-737 is a small molecule BH3 mimetic that binds tightly to a hydrophobic cleft on Bcl-2 and Bcl-XL and exerts its proapoptotic function by preventing antiapoptotic Bcl-2 family members from sequestering activating BH3 proteins (Oltersdorf et al., Nature 2005). We have reported that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induces the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway (Konopleva et al., Cancer Cell 2006). The ABT-737 related clinical compound, ABT-263, is undergoing Phase I/II studies in chronic lymphocytic leukemia, with initial signs of clinical activity. However, the main side effect is thrombocytopenia resulting from inhibition of Bcl-XL. Hence, combinations of ABT-737 with non-cytotoxic agents are desirable to take full advantage of ABT236's unique spectrum of biophysical and preclinical activities. In this project, we studied pharmacologic interactions between ABT-737 and the DNA methyltransferase inhibitor 5-azacytidine (5-azaC). 5-azaC is a cytidine analog with clinical activity in myelodysplastic syndromes (MDS) and in AML. Since recent studies indicate that 5-azaC induce DNA damage in p53-dependent fashion, we tested the hypothesis that the pro-apoptotic effects of 5-azaC/ABT-737 combination are related to non-redundant activation of BH3-only proteins and mitochondrial apoptosis in AML cells with wt p53. In vitro, 5-azaC and ABT-737 in combination for 72 hrs induced growth inhibition and apoptosis in AML cell lines OCI-AML3, MOLM-13 and U937 in a highly synergistic, dose-dependent fashion, with combination indices (CIs) ranging from 0.1 to 0.22. These effects were observed even at low concentrations (5-azaC 100nM and ABT-737 10nM, at 10:1 ratio). In contrast, no synergistic apoptosis was seen in p53-null HL-60 cells. Likewise, ABT-737/5-azaC induced apoptosis in a synergistic fashion in OCI-AML3 cells infected with vector control shRNA (CI=0.04) but failed to induce cell death in OCI-AML3 p53 shRNA cells, indicating critical p53-dependent mechanisms of cell death. In primary AML samples sensitive to ABT-737 alone (n=3), synergistic and additive effects were seen. The combined effects of 5-azaC and ABT-737 were further investigated in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice injected with cells from a patient with primary refractory AML. Seven days after leukemia transplantation, mice were treated with vehicle, ABT-737 (intraperitoneally (IP), 75mg/kg/day for 10 days), 5-azacytidine (IP, 4mg/kg/day for 5 days) or with the combination. Engraftment of patient leukemia cells was analyzed by the immunohistochemical detection of CD45-positive cells in bone marrow and spleen seven weeks after transplantation. Both, ABT-737 and 5azaC each exerted anti-leukemic effects, as evidenced by significant reduction in leukemia cells in bone marrow and spleen (10% and 3% CD45+ cells detectable in 1/3 mice in ABT-737 and 5-azaC groups, respectively), no CD45+ AML cells were detected in organs of 3/3 mice treated with the combination. No overt hemorrhage was detected in the animals. In summary, the combination of 5-azaC and ABT-737 induces synergistic cells death in AML cell lines and in a subset of primary AML samples in a p53-dependent fashion. The mechanisms of this pharmacologic interactions including the p53-dependent upregulation of BH3-only proteins, described by us for ABT-737/MDM2 inhibitor combinations, are currently under investigation. Results suggest that this therapeutic strategy can be successfully utilized in AML patients with low mutation rate and unimpaired signaling of p53. Disclosures: No relevant conflicts of interest to declare." @default.
• W2980032444 created "2019-10-18" @default.
• W2980032444 creator A5004888325 @default.
• W2980032444 creator A5019469702 @default.
• W2980032444 creator A5022647201 @default.
• W2980032444 creator A5036260755 @default.
• W2980032444 creator A5043947276 @default.
• W2980032444 creator A5052186917 @default.
• W2980032444 creator A5091058254 @default.
• W2980032444 date "2010-11-19" @default.
• W2980032444 modified "2023-09-30" @default.
• W2980032444 title "The Synergistic Effect of DNA Methylation Inhibitor 5-Azacytidine and Bcl-2 Signaling Blockade ABT-737 Combination Treatment Induce Apoptosis In AML" @default.
• W2980032444 doi "https://doi.org/10.1182/blood.v116.21.3311.3311" @default.
• W2980032444 hasPublicationYear "2010" @default.
• W2980032444 type Work @default.
• W2980032444 sameAs 2980032444 @default.
• W2980032444 citedByCount "0" @default.
• W2980032444 crossrefType "journal-article" @default.
• W2980032444 hasAuthorship W2980032444A5004888325 @default.
• W2980032444 hasAuthorship W2980032444A5019469702 @default.
• W2980032444 hasAuthorship W2980032444A5022647201 @default.
• W2980032444 hasAuthorship W2980032444A5036260755 @default.
• W2980032444 hasAuthorship W2980032444A5043947276 @default.
• W2980032444 hasAuthorship W2980032444A5052186917 @default.
• W2980032444 hasAuthorship W2980032444A5091058254 @default.
• W2980032444 hasConcept C104317684 @default.
• W2980032444 hasConcept C109159458 @default.
• W2980032444 hasConcept C121608353 @default.
• W2980032444 hasConcept C150194340 @default.
• W2980032444 hasConcept C154317977 @default.
• W2980032444 hasConcept C190283241 @default.
• W2980032444 hasConcept C190727270 @default.
• W2980032444 hasConcept C201750760 @default.
• W2980032444 hasConcept C202751555 @default.
• W2980032444 hasConcept C203014093 @default.
• W2980032444 hasConcept C2776239401 @default.
• W2980032444 hasConcept C2778461978 @default.
• W2980032444 hasConcept C2778729363 @default.
• W2980032444 hasConcept C2779282312 @default.
• W2980032444 hasConcept C2780007613 @default.
• W2980032444 hasConcept C2780817109 @default.
• W2980032444 hasConcept C28328180 @default.
• W2980032444 hasConcept C502942594 @default.
• W2980032444 hasConcept C54355233 @default.
• W2980032444 hasConcept C55493867 @default.
• W2980032444 hasConcept C555283112 @default.
• W2980032444 hasConcept C86803240 @default.
• W2980032444 hasConcept C95444343 @default.
• W2980032444 hasConceptScore W2980032444C104317684 @default.
• W2980032444 hasConceptScore W2980032444C109159458 @default.
• W2980032444 hasConceptScore W2980032444C121608353 @default.
• W2980032444 hasConceptScore W2980032444C150194340 @default.
• W2980032444 hasConceptScore W2980032444C154317977 @default.
• W2980032444 hasConceptScore W2980032444C190283241 @default.
• W2980032444 hasConceptScore W2980032444C190727270 @default.
• W2980032444 hasConceptScore W2980032444C201750760 @default.
• W2980032444 hasConceptScore W2980032444C202751555 @default.
• W2980032444 hasConceptScore W2980032444C203014093 @default.
• W2980032444 hasConceptScore W2980032444C2776239401 @default.
• W2980032444 hasConceptScore W2980032444C2778461978 @default.
• W2980032444 hasConceptScore W2980032444C2778729363 @default.
• W2980032444 hasConceptScore W2980032444C2779282312 @default.
• W2980032444 hasConceptScore W2980032444C2780007613 @default.
• W2980032444 hasConceptScore W2980032444C2780817109 @default.
• W2980032444 hasConceptScore W2980032444C28328180 @default.
• W2980032444 hasConceptScore W2980032444C502942594 @default.
• W2980032444 hasConceptScore W2980032444C54355233 @default.
• W2980032444 hasConceptScore W2980032444C55493867 @default.
• W2980032444 hasConceptScore W2980032444C555283112 @default.
• W2980032444 hasConceptScore W2980032444C86803240 @default.
• W2980032444 hasConceptScore W2980032444C95444343 @default.
• W2980032444 hasLocation W29800324441 @default.
• W2980032444 hasOpenAccess W2980032444 @default.
• W2980032444 hasPrimaryLocation W29800324441 @default.
• W2980032444 hasRelatedWork W2017190603 @default.
• W2980032444 hasRelatedWork W2269888391 @default.
• W2980032444 hasRelatedWork W2340300548 @default.
• W2980032444 hasRelatedWork W2554093659 @default.
• W2980032444 hasRelatedWork W2558250642 @default.
• W2980032444 hasRelatedWork W2559785814 @default.
• W2980032444 hasRelatedWork W2573438812 @default.
• W2980032444 hasRelatedWork W2576782710 @default.
• W2980032444 hasRelatedWork W2577290629 @default.
• W2980032444 hasRelatedWork W2582501737 @default.
• W2980032444 hasRelatedWork W2587823957 @default.
• W2980032444 hasRelatedWork W2590616116 @default.
• W2980032444 hasRelatedWork W2591380092 @default.
• W2980032444 hasRelatedWork W2739894552 @default.
• W2980032444 hasRelatedWork W2767056524 @default.
• W2980032444 hasRelatedWork W2910650023 @default.
• W2980032444 hasRelatedWork W2979471830 @default.
• W2980032444 hasRelatedWork W2979820519 @default.
• W2980032444 hasRelatedWork W2980245895 @default.
• W2980032444 hasRelatedWork W65177702 @default.
• W2980032444 isParatext "false" @default.
• W2980032444 isRetracted "false" @default.
• W2980032444 magId "2980032444" @default.
• W2980032444 workType "article" @default.