title: Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation.
abstract: The multiple myeloma (MM) bone marrow (BM) microenvironment plays a critical role in supporting tumor growth and survival as well as in promoting formation of osteolytic lesions. Recent results suggest that the p38 mitogen-activated protein kinase (MAPK) is an important factor in maintaining this activated environment. In this report, we demonstrate that the p38alpha MAPK inhibitor, SCIO-469, suppresses secretion of the tumor-supportive factors IL-6 and VEGF from BM stromal cells (BMSCs) as well as cocultures of BMSCs with MM cells, resulting in reduction in MM cell proliferation. Additionally, we show that SCIO-469 prevents TNFalpha-induced adhesion of MM cells to BMSCs through an ICAM-1- and VCAM-1-independent mechanism. Microarray analysis revealed a novel set of TNFalpha-induced chemokines in BMSCs that is strongly inhibited by SCIO-469. Furthermore, reintroduction of chemokines CXCL10 and CCL8 to BMSCs overcomes the inhibitory effect of SCIO-469 on TNFalpha-induced MM adhesion. Lastly, we show that SCIO-469 inhibits secretion and expression of the osteoclast-activating factors IL-11, RANKL, and MIP-1alpha as well as prevents human osteoclast formation in vitro. Collectively, these results suggest that SCIO-469 treatment can suppress factors in the bone marrow microenvironment to inhibit MM cell proliferation and adhesion and also to alleviate osteolytic activation in MM.
authors.affiliation: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Stebbins
authors.forename: Margaret
authors.initials: M
authors.lastname: Henson
authors.forename: Gilbert
authors.initials: G
authors.lastname: O'Young
authors.forename: Sun J
authors.initials: SJ
authors.lastname: Choi
authors.forename: Diana
authors.initials: D
authors.lastname: Quon
authors.forename: Debby
authors.initials: D
authors.lastname: Damm
authors.forename: Mamatha
authors.initials: M
authors.lastname: Reddy
authors.forename: Jing Y
authors.initials: JY
authors.lastname: Ma
authors.forename: Edwin
authors.initials: E
authors.lastname: Haghnazari
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Medicherla
authors.forename: Andy
authors.initials: A
authors.lastname: Protter
authors.forename: George F
authors.initials: GF
authors.lastname: Schreiner
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kurihara
authors.forename: Judy
authors.initials: J
authors.lastname: Anderson
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.forename: Tony A
authors.initials: TA
authors.lastname: Navas
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018925:Chemokines; D017077:Culture Media, Conditioned; D007211:Indoles; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C499748:SCIO-469; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases