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p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications
Authors: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
Affiliation:Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA;, Department of Internal Medicine, Division of Hematology and Oncology, Fukuoka University, Fukuoka, Japan;, Orthopaedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Boston, MA, USA;, and Eli Lilly Company, Lilly Corporate Center, Indianapolis, IN, USA
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.
Keywords:multiple myeloma    microenvironment    p38 mitogen-activated protein kinase    osteoclastogenesis    LY2228820
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