Dataset Information

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL? leukemia cells.

ABSTRACT: Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

SUBMITTER: Nguyen T

PROVIDER: S-EPMC4413916 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.

Nguyen Tri T Hawkins Elisa E Kolluri Akhil A Kmieciak Maciej M Park Haeseong H Lin Hui H Grant Steven S

Leukemia research 20141111 1

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRN ...[more]

PMID: 25465126

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Project description:Imatinib mesylate is a tyrosine kinase inhibitor that was approved by the U.S. Food and Drug Administration in 2001 for treatment of many different stages of chronic myeloid leukemia and in 2002 for treatment of gastrointestinal stromal tumors. Imatinib is known to inhibit the dysregulated proliferation of chronic myeloid leukemia, which is associated with the Bcr-Abl kinase; in gastrointestinal stromal tumors, imatinib is known to act via c-Kit kinase inhibition. The objective of this study was to synthesize an (18)F-labeled analog of imatinib not as a primary imaging agent but rather as a tracer for in vivo drug distribution and tracer concentration that can be used as a PET imaging surrogate for imatinib.Molecular modeling studies based on the crystal structure of imatinib bound to the active site of Abl were performed for designing the fluorinated analog. A 2-fluoroethyl analog of imatinib (SKI696) was synthesized using well-established procedures. The selectivity and binding affinity of SKI696 were compared with those of imatinib in vitro. Mice bearing K562 tumor xenografts, which are known to overexpress Bcr-Abl, were imaged with (18)F-SKI696 PET. A biodistribution study was also performed on K562 tumor-bearing mice to which our radiolabeled tracer was administered.The kinase assay verified that imatinib and SKI696 bind to the same targets with similar affinities. The feasibility of using (18)F-SKI696 as a PET agent was examined in vivo, and (18)F-SKI696 PET was shown to visualize K562 tumor xenografts in nude mice. The tumor was visible on PET 1 h after injection, with uptake of 1% of the injected dose. Biodistribution studies in K562-bearing mice were also performed, and the uptake of (18)F-SKI696 (percentage injected dose per gram) for each organ was calculated.The results of the binding assay showed that SKI696 has selectivity and binding affinity comparable to imatinib. Small-animal PET of K562 tumor-bearing mice using (18)F-SKI696 as a PET agent displayed promising tumor uptake and tumor-to-nontarget contrast. Because (18)F-SKI696 has been taken up in vivo by tumors that overexpress Bcr-Abl, we are exploring a possible role for identifying tumors that will respond to imatinib before therapy.

Dataset Information

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL? leukemia cells.

Publications

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.

Similar Datasets

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