A p38 MAPK inhibitor
SCIO 469 is a p38 MAPK inhibitor (IC50 = 9 nM for p38α).1 It is 10-fold selective for p38α over p38β MAPK and 2,000-fold selective over a panel of 20 additional kinases. SCIO 469 inhibits secretion of IL-6 from multiple myeloma patient-derived bone marrow stromal cells (BMSCs) in a concentration-dependent manner. It increases growth inhibition, DNA fragmentation, and caspase-8 and PARP cleavage induced by the proteasome inhibitor PS-341 in MM.1S cells when used at concentrations of 100 and 200 nM. SCIO 469 (150 and 450 mg/kg) reduces microvessel density and tumor load and increases survival in a 5T33MM murine myeloma model.2
1.Hideshima, T., Podar, K., Chauhan, D., et al.p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cellsOncogene23(54)8766-8776(2004) 2.Vanderkerken, K., Medicherla, S., Coulton, L., et al.Inhibition of p38α mitogen-activated protein kinase prevents the development of osteolytic bone disease, reduces tumor burden, and increases survival in murine models of multiple myelomaCancer Res.67(10)4572-4577(2007)
Cell experiment: | 5TMM cells (0.5 × 106/mL) were pretreated with different concentrations of Talmapimod (SCIO-469) in serum-free medium and then placed in the lower compartment of a Transwell system. Syngeneic bone marrow stromal cells were seeded into the Transwell itself. After 18 h, the 5TMM cells were collected from the lower compartment and stained for active caspase-3 with a FITC-labeled antibody according to manufacturer's instructions |
Animal experiment: | Animal injection[1]For studies of the effect of Talmapimod (SCIO-469) on myeloma development, three groups of male mice (n = 12) were injected i.v. with 0.5 × 106 5T33MM cells. Mice were left untreated (naive) or, if injected with tumor cells, treated from the time of tumor cells injection with either Talmapimod (SCIO-469) (150 or 450 mg/kg powder diet continuously available for the mice) or a vehicle (PBS) until the first mice showed signs of morbidity (at 3.7 weeks). |
参考文献: [1]. Hideshima T et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene. 2004 Nov 18, 23(54), 8766-76. | |
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