p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications

Br J Haematol. 2008 May;141(5):598-606. doi: 10.1111/j.1365-2141.2008.07044.x. Epub 2008 Apr 7.

Abstract

The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment induces proliferation and survival of MM cells, as well as osteoclastogenesis. This study investigated the therapeutic potential of novel p38 mitogen-activated protein kinase (p38MAPK) inhibitor LY2228820 (LY) in MM. Although cytotoxicity against MM cell lines was modest, LY significantly enhanced the toxicity of bortezomib by down-regulating bortezomib-induced heat shock protein 27 phosphorylation. LY inhibited interleukin-6 secretion from long term cultured-BM stromal cells and BM mononuclear cells (BMMNCs) derived from MM patients in remission. LY also inhibited macrophage inflammatory protein-1alpha secretion from patient MM cells and BMMNCs as well as normal CD14 positive osteoclast precursor cells. Moreover, LY significantly inhibited in vitro osteoclastogenesis from CD14 positive cells induced by macrophage-colony stimulating factor and soluble receptor activator of nuclear factor-kappaB ligand. Finally, LY also inhibited in vivo osteoclatogenesis in a severe combined immunodeficiency mouse model of human MM. These results suggest that LY represents a promising novel targeted approach to improve MM patient outcome both by enhancing the effect of bortezomib and by reducing osteoskeletal events.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Death / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Heat-Shock Proteins / metabolism
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, SCID
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology*
  • Neoplasm Transplantation
  • Osteoclasts / drug effects*
  • Phosphorylation / drug effects
  • Pyrazines / pharmacology*
  • Pyridines / pharmacology*
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Heat-Shock Proteins
  • Imidazoles
  • LY2228820
  • Pyrazines
  • Pyridines
  • Bortezomib
  • p38 Mitogen-Activated Protein Kinases