title: p38alpha-selective MAP kinase inhibitor reduces tumor growth in mouse xenograft models of multiple myeloma.
abstract: Multiple myeloma (MM) is a clonal plasma cell malignancy, which is currently incurable. Therefore, new mono- or combined therapy treatment regimens in the early and advanced phases of MM are urgently needed to combat this disease. Recently, p38 mitogen-activated protein kinase (MAPK) has been implicated as playing an important role in MM. Therefore, the effect of a p38alpha-selective MAPK inhibitor, SCIO-469 (indole-5-carboxamide, ATP-competitive inhibitor), or its structural analog, SD-282 (indole-5-carboxamide, ATP-competitive inhibitor) was examined in mouse xenograft models of MM using human RPMI-8226 or H-929 plasmacytoma inocula. Oral treatment with SCIO-469 (10, 30, 90 mg/kg) twice daily was initiated in mice with palpable tumors of RPMI-8226 origin, a condition that mimics early human myeloma disease. In mice with palpable tumors, 14 days of SCIO-469 treatment significantly reduced RPMI-8226 tumor growth in a dose-dependent manner. A significant dose-dependent reduction in RPMI-8226 tumor growth was also observed when SCIO-469 oral treatment at doses of 10, 30 and 90 mg/kg twice daily was initiated in mice with tumors of pronounced size, a condition that mimics advanced human myeloma disease. In a similar set of studies employing the SCIO-469 analogue SD-282 at 90 mg/kg/bid orally, histological assessment at the end of the study demonstrated a significant reduction in RPMI-8226 tumor growth and angiogenesis. SD-282 treatment was additionally shown to significantly reduced expression of heat-shock protein-27 (HSP-27) and phospho-p38 in the tumor cells. Furthermore, co-administration of SCIO-469 with dexamethasone elicited antitumor properties in dexamethasone-sensitive H-929 tumors at much lower than the typically effective doses of dexamethasone, suggesting its potential for combined therapy. In conclusion, p38 inhibitors reduced human myeloma cell growth in vivo both at early and advanced phases of the disease. The current study also provides evidence of potential for co-therapy with dexamethasone.
authors.affiliation: Scios Inc, Fremont, CA 94555, USA. satya.medicherla@spcorp.com
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Medicherla
authors.forename: Mamatha
authors.initials: M
authors.lastname: Reddy
authors.forename: Jing
authors.initials: J
authors.lastname: Ying
authors.forename: Tony A
authors.initials: TA
authors.lastname: Navas
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Nirupama
authors.initials: N
authors.lastname: Hanjarappa
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; C499748:SCIO-469; C514526:indole-5-carboxamide; D003907:Dexamethasone; D048308:Mitogen-Activated Protein Kinase 14