PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects
| Autor: | Doriano Fabbro, Alexandra Böhm, Winfried F. Pickl, Karoline V. Gleixner, Karoline Sonneck, Peter Valent, Matthias Mayerhofer, Karl J. Aichberger, Christian Sillaber, Sophia Derdak, Paul W. Manley, Puchit Samorapoompichit, Alexander Gruze |
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| Rok vydání: | 2006 |
| Předmět: |
Immunology
CD2 Antigens Drug Evaluation Preclinical Down-Regulation Apoptosis Leukemia Mast-Cell Platelet Membrane Glycoproteins In Vitro Techniques Biology Biochemistry Piperazines Immunophenotyping Antigens CD Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Phosphorylation Systemic mastocytosis Cladribine Cells Cultured Protein Kinase C Cell Proliferation Tetraspanin 30 Drug Synergism Imatinib Cell Biology Hematology Middle Aged Staurosporine medicine.disease Mast cell leukemia Anti-Bacterial Agents Proto-Oncogene Proteins c-kit Leukemia Pyrimidines Imatinib mesylate Nilotinib Doxycycline Benzamides Mutation Imatinib Mesylate Cancer research Female Tyrosine kinase medicine.drug |
| Zdroj: | Blood. 107:752-759 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | In most patients with systemic mastocytosis (SM), including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic KIT mutation D816V. KIT D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive drug target. However, imatinib and most other TK inhibitors fail to block the TK activity of KIT D816V. We show that the novel TK-targeting drugs PKC412 and AMN107 counteract TK activity of D816V KIT and inhibit the growth of Ba/F3 cells with doxycycline-inducible expression of KIT D816V as well as the growth of primary neoplastic mast cells and HMC-1 cells harboring this KIT mutation. PKC412 was a superior agent with median inhibitory concentration (IC50) values of 50 to 250 nM without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited more potent effects in KIT D816V- HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or D816V-mutated KIT. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with induction of apoptosis and down-regulation of CD2 and CD63. PKC412 was found to cooperate with AMN107, imatinib, and cladribine (2CdA) in producing growth inhibition in HMC-1, but synergistic drug interactions were observed only in cells lacking KIT D816V. Together, PKC412 and AMN107 represent promising novel agents for targeted therapy of SM. (Blood. 2006;107: 752-759) |
| Databáze: | OpenAIRE |
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