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

Overview

MeSH Major

  • Benzimidazoles
  • Janus Kinases
  • Multiple Myeloma
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyridones

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.

publication date

  • October 2006

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-05-4280

PubMed ID

  • 17018630

Additional Document Info

start page

  • 9714

end page

  • 21

volume

  • 66

number

  • 19