A modified DAW-22 compound F-B1 inhibits Bcr/Abl and induces apoptosis in chronic myelogenous leukemia cells.

The Bcr/Abl kinase is an oncogenic fusion protein that plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Some small-molecule kinase inhibitors such as imatinib were developed in the treatment of CML; however, resistant to imatinib is an emerging problem of CML therapy. Hence, additional approaches or compounds targeting leukemogenic cells are required. F-B1 is a new compound obtained by modifying DAW-22, a natural sesquiterpenoid coumarin, which was isolated from traditional Chinese medicine Ferula ferulaeoides (Steud.) Korov. F-B1 was found to inhibit the growth of myelogenous leukemia cell lines, that is, K562 cells bearing wild-type Bcr/Abl and imatinib-resistant K562G cells. F-B1 potently down-regulated the mRNA and protein levels of Bcr/Abl, followed by suppression of the downstream molecules such as Akt, externally regulated kinases, and nuclear factor κB. In addition, F-B1 also induced cell apoptosis by impairing the balance between proapoptotic protein Bax and antiapoptotic proteins Bcl-2 and Bcl-XL and increased the activity of mitochondrial-dependent apoptosis in nude mouse xenografts. Experimental validation results together demonstrated that F-B1 can inhibit Bcr/Abl fusion proteins in K562 and K562G cells, implying that F-B1 might be a promising drug to treat CML, especially the imatinib-resistant CML.