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

• Published in: British journal of haematology Vol. 141; no. 5; pp. 598 - 606
• Main 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.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2008; Blackwell
• Subjects: Animals; Antineoplastic Agents; Biological and medical sciences; Boronic Acids - pharmacology; Bortezomib; Cell Death - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Heat-Shock Proteins - metabolism; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Imidazoles - pharmacology; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; LY2228820; MAP Kinase Signaling System - drug effects; Medical sciences; Mice; Mice, SCID; microenvironment; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Transplantation; osteoclastogenesis; Osteoclasts - drug effects; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - physiology; p38 mitogen‐activated protein kinase; Phosphorylation - drug effects; Pyrazines - pharmacology; Pyridines - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Immunopathology; multiple myeloma; Bortezomib; Hematology; Cytotoxicity; Malignant hemopathy; Microenvironment; Myeloma; Osteoclastogenesis; Treatment; Immunoglobulinopathy; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Dipeptides; p38 Mitogen activated protein kinase; p38 mitogen-activated protein kinase; LY2228820; Cancer
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2008.07044.x

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.