Pyridone 6, a Pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells Journal Article

Authors: Pedranzini, L.; Dechow, T.; Berishaj, M.; Comenzo, R.; Zhou, P.; Azare, J.; Bornmann, W.; Bromberg, J.
Article Title: Pyridone 6, a Pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells
Abstract: Interleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of multiple myeloma. Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor, tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived cell lines. P6 induced growth arrest and subsequent apoptosis of the IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown either in IL-6-containing medium or in the presence of bone marrow-derived stromal cells (BMSC) using much lower concentrations of drug and with significantly faster kinetics than AG490. Myeloma-derived cell lines, which either express constitutively activated JAK/signal transducers and activators of transcription (STAT) 3 (U266) or are IL-6 growth stimulated (KMS11), are partially growth inhibited by P6. However, P6 does not inhibit the growth of myeloma-derived cell lines lacking activated JAKs/STATs nor does it inhibit mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase activity compared with AG490, which led to activation of ERK and induced robust apoptosis of all the examined cell lines. Finally, P6 inhibited the growth of primary myeloma patient samples grown in the presence of BMSCs. Thus, P6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs. ©2006 American Association for Cancer Research.
Keywords: mitogen activated protein kinase; unclassified drug; janus kinase inhibitor; drug activity; nonhuman; animal cell; mouse; animals; mice; stat3 protein; apoptosis; enzyme inhibition; multiple myeloma; map kinase signaling system; neoplasm proteins; enzyme activation; drug screening assays, antitumor; enzyme activity; cell line, tumor; drug specificity; pyridones; phosphorylation; protein kinase inhibitors; cancer inhibition; enzyme phosphorylation; protein processing, post-translational; drug mechanism; janus kinase; interleukin 6; interleukin-6; extracellular signal-regulated map kinases; stat3 transcription factor; hybridoma; stroma cell; stromal cells; drug sensitivity; benzimidazoles; myeloma; growth disorder; coculture techniques; tyrphostins; myeloma cell; hybridomas; janus kinases; n benzyl 2 cyano 3 (3,4 dihydroxyphenyl)acrylamide; pyridone 6; pyridone derivative
Journal Title: Cancer Research
Volume: 66
Issue: 19
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2006-10-01
Start Page: 9714
End Page: 9721
Language: English
DOI: 10.1158/0008-5472.can-05-4280
PUBMED: 17018630
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 67" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Janeen R Azare
    7 Azare
  2. Jacqueline Bromberg
    104 Bromberg
  3. Raymond L Comenzo
    112 Comenzo
  4. Ping Zhou
    43 Zhou