p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications.
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.
Ishitsuka
Kenji
K
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Hideshima
Teru
T
Neri
Paola
P
Vallet
Sonia
S
Shiraishi
Norihiko
N
Okawa
Yutaka
Y
Shen
Zhenxin
Z
Raje
Noopur
N
Kiziltepe
Tanyel
T
Ocio
Enrique M
EM
Chauhan
Dharminder
D
Tassone
Pierfrancesco
P
Munshi
Nikhil
N
Campbell
Robert M
RM
Dios
Alfonso De
AD
Shih
Chuan
C
Starling
James J
JJ
Tamura
Kazuo
K
Anderson
Kenneth C
KC
D000818:Animals; D000970:Antineoplastic Agents; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D006360:Heat-Shock Proteins; D007093:Imidazoles; D011719:Pyrazines; D011725:Pyridines; D000069286:Bortezomib; C580958:ralimetinib; D048051:p38 Mitogen-Activated Protein Kinases