Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells
| Autor: | Lihui Lu, Bruce D. Dorsey, Bruce Ruggeri, Mark S. Albom, Matthew R. Quail, Thelma S. Angeles, Reddy Dandu R, Linda Weinberg, Mangeng Cheng, Nadine C. Becknell, Mark A. Ator, Beverly P. Holskin, Weihua Wan, Sheryl L. Meyer, Robert L. Hudkins, Ted L. Underiner |
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| Rok vydání: | 2005 |
| Předmět: |
Indazoles
Cell Survival Immunology Carbazoles Apoptosis Enzyme-Linked Immunosorbent Assay Biology Biochemistry hemic and lymphatic diseases Cell Line Tumor medicine Anaplastic lymphoma kinase Humans Anaplastic Lymphoma Kinase Anaplastic large-cell lymphoma Protein kinase B Interleukin 3 Cell growth Phenylurea Compounds Receptor Protein-Tyrosine Kinases Cell Biology Hematology Protein-Tyrosine Kinases medicine.disease Flow Cytometry Gene Expression Regulation Neoplastic Cell culture Caspases Cancer research Lymphoma Large B-Cell Diffuse Signal transduction Cell Division K562 cells |
| Zdroj: | Blood. 107(4) |
| ISSN: | 0006-4971 |
| Popis: | The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis. |
| Databáze: | OpenAIRE |
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