Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells

• Published in: Toxicology in vitro Vol. 23; no. 6; pp. 979 - 985
• Main Authors: Huang, Yu-Chuen, Chao, David K., Clifford Chao, K.S., Chen, Yu-Jen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2009
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Differentiation; Dose-Response Relationship, Drug; Humans; K562 Cells; Leukemia - drug therapy; Leukemia - metabolism; Megakaryocyte; Megakaryocytes - metabolism; Midostaurin; PKC412; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Receptors, Thrombopoietin - drug effects; Receptors, Thrombopoietin - metabolism; Signal Transduction - drug effects; Staurosporine - administration & dosage; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Time Factors; Up-Regulation - drug effects; Megakaryocyte; Midostaurin; Differentiation; PKC412; Apoptosis
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2009.06.027

Midostaurin (PKC412), a small-molecule multiple tyrosine kinase inhibitor, has been shown to suppress the growth of various tumor cells. Since kinases inhibited by midostaurin are involved in megakaryocytic differentiation, we hypothesized that this novel target therapeutic might have a role in the treatment of human leukemia cells. Hence, we examined the effect of midostaurin on human erythroleukemia cells and evaluated potential mechanisms. Midostaurin inhibited the growth of both K562 and HEL cells in dose- and time-dependent manner. Morphological changes such as enlarged contours, multipolarity of mitotic spindles, and multinucleation of megakaryocytes were noted in both cell lines treated by midostaurin. A smaller population of apoptotic cells was also observed. DNA histogram revealed polyploid and hypoploid populations of midostaurin-treated cells. Midostaurin treatment enhanced the surface expression of the megakaryocytic marker CD61; in contrast, the erythroid marker glycophorin A expression was decreased. At optimal conditions for inducing megakaryocytic differentiation, midostaurin upregulated the expression and signaling of c-Mpl, a thrombopoietin receptor-encoding gene, in HEL cells. These results indicate that midostaurin can inhibit growth; induce megakaryocytic differentiation; and to a lesser extent, cause apoptosis in HEL cells. This effect might involve the expression and signaling of c-Mpl.