benzofurans and tanespimycin

17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90, results in cell type-specific inhibition of proliferation of leukemic cells. GTP14564 is a tyrosine kinase inhibitor actively against FLT3. The current study evaluated the single and combined effects of 17-AAG and GTP14564, and the role of FLT3 in their inhibitory effects. The importance of FLT3 mutations was demonstrated using small interfering RNA (siRNA) targeted to FLT3. Similar to FLT3 siRNA, GTP14564 inhibited FLT3 internal tandem duplication (ITD) cells (MV4;11) and FLT3 amplified wild-type cells (SEMK2-M1), but not wild-type FLT3 cells (RS4;11). However, when RS4;11 cells were stimulated with FLT3-ligand, phosphorylation of STAT5 and GTP14564 inhibition were observed. Responses to GTP14564 in all cell types were directly related to the level of STAT5 phosphorylation in the cells. We observed synergistic effects of combined 17-AAG and GTP14564 in cell lines with FLT3-ITD and amplified wild-type FLT3. Combined treatment with 17-AAG and GTP14564 reduced the levels of p-FLT3 and p-STAT5, enhanced G0/G1 arrest and apoptosis in FLT3-ITD and amplified wild-type FLT3. The combination of 17-AAG with FLT3 kinase inhibitors can enhance targeted therapy in leukemias with FLT3 mutations, such as MLL fusion gene leukemias.

Topics: Apoptosis; Benzofurans; Benzoquinones; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Leukemic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Leukemia; Ligands; Milk Proteins; Mutation; Phosphorylation; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Rifabutin; RNA, Small Interfering; Sensitivity and Specificity; Signal Transduction; STAT5 Transcription Factor; Trans-Activators