Abstract
The effects of the multikinase inhibitor sorafenib (BAY 43-9006), an agent shown previously to induce apoptosis in human leukemia cells through inhibition of myeloid cell leukemia-1 (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 signal transducer and activator of transcription (STAT) 5 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 eukaryotic initiation factor 4E as wild-type cells. Finally, stable knockdown of Bcl-2-interacting mediator of cell death (Bim) with short hairpin RNA in K562 cells significantly diminished sorafenib lethality, arguing strongly for a functional role of this proapoptotic Bcl-2 family member in the lethality of this agent. Together, these findings suggest that sorafenib effectively induces apoptosis in highly imatinib-resistant chronic myelogenous leukemia cells, most likely by inhibiting or down-regulating targets (i.e., STAT5 and Mcl-1) downstream or independent of Bcr/Abl.
Footnotes
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This work was supported by awards CA63753, CA93738, and CA100866 from the National Cancer Institute, award 6045-03 from the Leukemia and Lymphoma Society of America, an award from the V Foundation, and an award from the Department of Defense.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.033308.
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ABBREVIATIONS: CML, chronic myelogenous leukemia; IM, imatinib mesylate; ERK, extracellular regulated kinase; MEK, mitogen-activated extracellular-regulated kinase; STAT, signal transducer and activator of transcription; Mcl-1, myeloid cell leukemia-1; eIF4E, eukaryotic initiation factor 4E; Bim, Bcl-2-interacting mediator of cell death; shRNA, short hairpin RNA; PARP, poly(ADP-ribose) polymerase; JAK2, Janus tyrosine kinase; CEL, chronic eosinophilic leukemia; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; BAY 43-9006, 4-(4-(3-(4-chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxyllic acid methyamide-4-methylbenzenesulfonate; AMN107, 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; BMS-354825, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide; VX-680, cyclopropanecarboxylic acid N-(4-((4-(4-methylpiperazin-1-yl)-6-(5-methyl-2H-pyrazol-3-ylamino)pyrimidin-2-yl)sulfanyl)phenyl)amide; STI571, α-(4-methyl-1-piperazinyl)-3′-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide; NSC680410, adaphostin; PD184352, 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene.
- Received December 8, 2006.
- Accepted June 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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