Abstract

We studied anti-tumor effects of the class III receptor tyrosine kinase inhibitor SU11248 against a wide variety of hematological malignancies including the following leukemias: acute myeloid (THP-1, U937, Kasumi-1, MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, -2), blast crisis of chronic myeloid (KU812, Kcl-22, K562) and adult T-cell (MT-1, -2, -4), as well as, non-Hodgkin’s lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine-uptake studies showed that SU11248 was active against MV4-11 and Kasumi-1 cells which possessed activating mutations of the FLT-3 and the c-Kit gene, respectively, with IC50s of approximately 30 nM. In addition, SU11248 inhibited the proliferation of Bcr/Abl-expressing KU812, Kcl-22, K562, PALL-1, and -2 cells with IC50s ranging from 2 to 5 uM. SU11248 induced apoptosis of these cells via activation of caspase 3 as measured by Annexin V staining and caspase assay. SU11248 inhibited phosphorylation of c-Abl and its downstream effectors Akt and STAT5 in these cells. Interestingly, mTOR inhibitor rapamycin enhanced the ability of SU11248 to inhibit the proliferation of Bcr/Abl-expressing cells. For example, SU11248 (2 uM, 48 h) or rapamycin (100 nM, 48 h) alone inhibited the proliferation of KU812 cells by 47 ± 6 % or 8 ± 6 %, respectively. When both were combined, their proliferation was inhibited by approximately 90 %. Furthermore, SU11248 (10 nM to 1 uM, 48 h) inhibited the proliferation of freshly-isolated leukemia cells from individuals with AML (15 cases) as well as Ph-positive ALL (1 case), who relapsed after treatment with conventional chemotherapy with imatinib. Profound growth inhibition by SU11248 (IC50s <10 nM) occurred in leukemia cells (4 cases) having an in-frame tandem duplications within the juxtamembrane region of FLT3 gene. Furthermore, rapamycin potentiated the anti-proliferative effects of SU11248 in the freshly-isolated leukemia cells. Taken together, SU11248 may be useful for treatment of individuals with variety of leukemias and the combination of SU11248 and rapamycin represents a promising novel treatment strategy.

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