Effects of lndirubin Derivatives on the FLT3 Activity and Growth of Acute Myeloid Leukemia Cell Lines

Indirubin is an active constituent of traditional Chinese preparations used for the treatment of chronic myelocytic leukemia (CML). In the present study, the inhibitory activity of indirubin and its derivatives toward Fms-like tyrosine kinase 3 (FLT3) was examined. Indirubin-3'-oxime (10) and 6-bromoindirubin-3'-oxime (BIO) had potent inhibitory activity against FLT3 (IC50 = 79 nM and 254 nM, respectively). We also tested the cytotoxicity of these compounds against acute myeloid leukemia cell lines: MV4;11 cells harboring a constitutively activated form of FLT3, and RS4;11 cells with wild-type FLT3. IO and BIO potently inhibited the growth of MV4;11 cells with IC50 values of 30 nM and 61 nM, respectively. Conversely, RS4;11 cells were far less sensitive to these compounds. IO arrested the cell cycle of MV4;11 cells at the G(1) phase, and increased the dead cell population at the sub-G(1) phase and annexin V-positive cells. From these results, derivatives of IO may have potential to be developed as antileukemic agents. Drug Dev Res 71:221-227, 2010. (C) 2010 Wiley-Liss, Inc.