التفاصيل البيبلوغرافية
العنوان:
Concurrent inhibition of Pim and FLT3 kinases enhances apoptosis of FLT3-ITD acute myeloid leukemia cells through increased Mcl-1 proteasomal degradation
المؤلفون:
Rossana Trotta , Manfred Kraus , Maria R. Baer , Karthika Natarajan , Eduardo Davila , Dennis Huszar , Patrick R. Baldwin , Kshama A. Doshi , Rena G. Lapidus , Mario Scarpa , Trevor J. Mathias , Shivani Kapoor , Adriana E. Tron , Danilo Perrotti
سنة النشر:
2017
مصطلحات موضوعية:
0301 basic medicine , Cancer Research , Proteome , Cell Survival , Apoptosis , Biology , Article , 03 medical and health sciences , chemistry.chemical_compound , Mice , 0302 clinical medicine , fluids and secretions , Proto-Oncogene Proteins c-pim-1 , hemic and lymphatic diseases , Cell Line, Tumor , Gene Duplication , MG132 , medicine , Animals , Humans , Benzothiazoles , Protein Kinase Inhibitors , Quizartinib , Cell Proliferation , Membrane Potential, Mitochondrial , Phenylurea Compounds , Myeloid leukemia , hemic and immune systems , medicine.disease , Myeloid Cell Leukemia Sequence 1 Protein , Leukemia , Leukemia, Myeloid, Acute , 030104 developmental biology , Oncology , chemistry , fms-Like Tyrosine Kinase 3 , 030220 oncology & carcinogenesis , Fms-Like Tyrosine Kinase 3 , Immunology , embryonic structures , Proteolysis , Cancer research , Proteasome inhibitor , Female , FLT3 Inhibitor , Reactive Oxygen Species , Protein Processing, Post-Translational , medicine.drug
الوصف:
Purpose: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo. Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor–induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234–47. ©2017 AACR.
اللغة:
English
URL الوصول:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13e820063b3bfac9e171485cfa0e7870 https://europepmc.org/articles/PMC6444348 /
Rights:
OPEN
رقم الانضمام:
edsair.doi.dedup.....13e820063b3bfac9e171485cfa0e7870
قاعدة البيانات:
OpenAIRE