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

Kenji Ishitsuka, Teru Hideshima, Paola Neri, Sonia Vallet, Norihiko Shiraishi, Yutaka Okawa, Zhenxin Shen, Noopur Raje, Tanyel Kiziltepe, Enrique M. Ocio, Dharminder Chauhan, Pierfrancesco Tassone, Nikhil Munshi, Robert M. Campbell, Alfonso De Dios, Chuan Shih, James J. Starling, Kazuo Tamura, Kenneth C. Anderson

Research output: Journal article (peer-reviewed)Journal article

45 Citations (Scopus)

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-1α 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-κB 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.

Original languageEnglish
Pages (from-to)598-606
Number of pages9
JournalBritish Journal of Haematology
Volume141
Issue number5
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Keywords

  • LY2228820
  • Microenvironment
  • Multiple myeloma
  • Osteoclastogenesis
  • p38 mitogen-activated protein kinase
  • Heat-Shock Proteins/metabolism
  • Neoplasm Transplantation
  • Hematopoietic Stem Cells/drug effects
  • Humans
  • Osteoclasts/drug effects
  • Dose-Response Relationship, Drug
  • Imidazoles/pharmacology
  • Pyrazines/pharmacology
  • Cell Death/drug effects
  • Tumor Cells, Cultured
  • Multiple Myeloma/drug therapy
  • Disease Models, Animal
  • Bortezomib
  • Boronic Acids/pharmacology
  • Antineoplastic Agents
  • Mice, SCID
  • Drug Synergism
  • MAP Kinase Signaling System/drug effects
  • Animals
  • p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • Mice
  • Phosphorylation/drug effects
  • Pyridines/pharmacology

ASJC Scopus subject areas

  • Hematology

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