The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival

0440110 - BFÚ 2015 GB eng J - Článek v odborném periodiku
Scuto, A. - Krejčí, Pavel … celkem 16 autorů
The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival.
Leukemia. Roč. 25, č. 3 (2011), s. 538-550. ISSN 0887-6924. E-ISSN 1476-5551
Institucionální podpora: RVO:68081707
Klíčová slova: HUMAN MULTIPLE-MYELOMA * BONE-MARROW MICROENVIRONMENT * PROTEIN-KINASE CASCADE
Kód oboru RIV: BO - Biofyzika
Impakt faktor: 9.561, rok: 2011

IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms. 11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms. 18, MM1. S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.
Trvalý link: http://hdl.handle.net/11104/0243238