Combined effects of FLT3 and NF-kappaB selective inhibitors on acute myeloid leukemia in vivo.

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Wang C, Lu J, Wang Y, Bai S, Wang Y, Wang L, Sheng G

Combined effects of FLT3 and NF-kappaB selective inhibitors on acute myeloid leukemia in vivo.

J Biochem Mol Toxicol. 2012 Jan;26(1):35-43. doi: 10.1002/jbt.20411. Epub 2011 Sep 16.

PubMed ID

21928377 [ View in PubMed

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Abstract

FMS-like tyrosine kinase 3 (FLT3) is an independent poor prognostic marker of acute myeloid leukemia (AML), and strategies that specifically target FLT3 are therefore of substantial interest. However, previous studies with FLT3 inhibitors as single agents in patients with AML showed few clinical responses. In the present study, combined effects of FLT3 selective inhibitor (SC-203048) and NF-kappaB selective inhibitor (Parthenolide, PTL) on AML xenograft tumor growth in vivo were examined, and the possible antitumor mechanisms by which SC-203048 and PTL affect AML xenograft tumor growth were also detected. Results showed that the tumor growth was strongly inhibited, and increased cell apoptosis was also observed after treatments, especially in the combination group; meanwhile, the expressions of FLT3, p65, cyclin D1, and Bc1-2 decreased significantly, and the expression of nuclear Silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) increased notably. All results indicate that synergism exists between FLT3 and NF-kappaB inhibitors, and inhibitors combination treatment may be a potential strategy for AML.