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p38 mitogen‐activated protein kinase inhibitor LY2228820 enhances bortezomib‐induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications
Author(s) -
Ishitsuka Kenji,
Hideshima Teru,
Neri Paola,
Vallet Sonia,
Shiraishi Norihiko,
Okawa Yutaka,
Shen Zhenxin,
Raje Noopur,
Kiziltepe Tanyel,
Ocio Enrique M.,
Chauhan Dharminder,
Tassone Pierfrancesco,
Munshi Nikhil,
Campbell Robert M.,
Dios Alfonso De,
Shih Chuan,
Starling James J.,
Tamura Kazuo,
Anderson Kenneth C.
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07044.x
Subject(s) - bortezomib , cancer research , bone marrow , stromal cell , cd14 , chemistry , medicine , biology , immunology , multiple myeloma , receptor
Summary 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.