The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells
| Autor: | Christopher J. Burns, Andrew Spencer, Tiffany Khong, Monaghan Katherine Anne |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
STAT3 Transcription Factor
Cancer Research Cell Blotting Western Apoptosis Bortezomib Bone Marrow Antineoplastic Combined Chemotherapy Protocols medicine Humans Phosphorylation STAT3 Extracellular Signal-Regulated MAP Kinases Protein kinase B Melphalan Cells Cultured Cell Proliferation biology Kinase Interleukin-6 Cell Cycle Hematology Janus Kinase 1 Boronic Acids Cell biology medicine.anatomical_structure Pyrimidines Oncology Pyrazines Benzamides biology.protein Stromal Cells Janus kinase Multiple Myeloma medicine.drug Signal Transduction |
| Zdroj: | Leukemia. 25(12) |
| ISSN: | 1476-5551 |
| Popis: | Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G(2)/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n=6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies. |
| Databáze: | OpenAIRE |
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