title: Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo.
abstract: Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38alpha, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X(L) and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in MM cells, suggesting great potential for co-therapy.
authors.affiliation: Scios, Inc., Fremont, CA, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Navas
authors.forename: A N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: T
authors.initials: T
authors.lastname: Hideshima
authors.forename: M
authors.initials: M
authors.lastname: Reddy
authors.forename: J Y
authors.initials: JY
authors.lastname: Ma
authors.forename: E
authors.initials: E
authors.lastname: Haghnazari
authors.forename: M
authors.initials: M
authors.lastname: Henson
authors.forename: E G
authors.initials: EG
authors.lastname: Stebbins
authors.forename: I
authors.initials: I
authors.lastname: Kerr
authors.forename: G
authors.initials: G
authors.lastname: O'Young
authors.forename: A M
authors.initials: AM
authors.lastname: Kapoun
authors.forename: S
authors.initials: S
authors.lastname: Chakravarty
authors.forename: B
authors.initials: B
authors.lastname: Mavunkel
authors.forename: J
authors.initials: J
authors.lastname: Perumattam
authors.forename: G
authors.initials: G
authors.lastname: Luedtke
authors.forename: S
authors.initials: S
authors.lastname: Dugar
authors.forename: S
authors.initials: S
authors.lastname: Medicherla
authors.forename: A A
authors.initials: AA
authors.lastname: Protter
authors.forename: G F
authors.initials: GF
authors.lastname: Schreiner
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.forename: L S
authors.initials: LS
authors.lastname: Higgins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018832:Molecular Chaperones; D009101:Multiple Myeloma / Q000201:enzymology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; D001897:Boronic Acids; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007211:Indoles; D007976:Leupeptins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; C499748:SCIO-469; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000069286:Bortezomib; D048308:Mitogen-Activated Protein Kinase 14; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde