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. Correspondence to Yanling Mu, MD, Key laboratory for Rare Disease of Shandong Province, Department of Pharmacology, Institute of Materia Medica, Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan 250062, China Tel/fax: +86 053 182 612 443; e-mail: myling501@hotmail.com Received August 6, 2018 Accepted October 18, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

from #Head and Neck by Sfakianakis via simeraentaxei on Inoreader https://ift.tt/2DllG51