Received for publication December 12, 2006.
Revised June 25, 2007.
Accepted for publication June 26, 2007.

THE MULTIKINASE INHIBITOR SORAFENIB INDUCES APOPTOSIS IN HIGHLY IMATINIB MESYLATE-RESISTANT BCR/ABL⁺ HUMAN LEUKEMIA CELLS IN ASSOCIATION WITH STAT5 INHIBITION AND MCL-1 DOWN-REGULATION

Abstract

The effects of the multi-kinase inhibitor BAY 43-9006 (sorafenib), an agent previously shown to induce apoptosis in human leukemia cells through inhibition of Mcl-1 translation, have been examined in Bcr/Abl⁺ leukemia cells resistant to imatinib mesylate (IM). When administered at pharmacologically relevant concentrations (10-15 µM), sorafenib potently induced apoptosis in imatinib mesylate-resistant cells expressing high levels of Bcr/Abl, cells exhibiting a Bcr/Abl-independent, Lyn-dependent form of resistance, and CD34⁺ cells obtained from imatinib-resistant patients. In addition, Ba/F3 cells expressing mutations rendering them resistant to IM (e.g., E255K, M351T) or to IM, dasatinib, and nilotinib (T315I) remained fully sensitive to sorafenib. Induction of apoptosis by sorafenib was associated with rapid and pronounced down-regulation of Mcl-1 and diminished STAT5 phosphorylation and reporter activity, but only very modest and delayed inactivation of the Bcr/Abl downstream target Crkl. Moreover, transfection with a constitutively active STAT5 construct partially but significantly protected cells from sorafenib lethality. Ba/F3 cells expressing Bcr/Abl mutations were as sensitive to sorafenib-induced Mcl-1 down-regulation and dephosphorylation of STAT5 and eIF4E as wild-type cells. Finally, stable knockdown of Bim with shRNA in K562 cells significantly diminished sorafenib lethality, arguing strongly for a functional role of this pro-apoptotic Bcl-2 family member in the lethalality of this agent. Together, these findings suggest that sorafenib effectively induces apoptosis in highly imatinib-resistant CML cells, most likely by inhibiting or downregulating targets (i.e., STAT5 and Mcl-1) downstream or independent of Bcr/Abl.

Key words: Jak/Stats, Raf family, MAP Kinase, Apoptosis

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