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SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo Uhl M; Aulwurm S; Wischhusen J; Weiler M; Ma JY; Almirez R; Mangadu R; Liu YW; Platten M; Herrlinger U; Murphy A; Wong DH; Wick W; Higgins LS; Weller MCancer Res 2004[Nov]; 64 (21): 7954-61The cytokine transforming growth factor (TGF)-beta, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-beta receptor (TGF-betaR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-beta-sensitive CCL64 cells mediated by recombinant TGF-beta1 or TGF-beta2 or of TGF-beta-containing glioma cell supernatant at an EC(50) of 0.1 mumol/L. SD-208 blocks autocrine and paracrine TGF-beta signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-beta reporter assays and strongly inhibits constitutive and TGF-beta-evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-beta-releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon gamma and tumor necrosis factor alpha by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-beta or of TGF-beta-containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-beta-induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-beta receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-beta activity.|Activin Receptors, Type I/*antagonists & inhibitors[MESH]|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Cell Division/drug effects[MESH]|Cell Line, Tumor[MESH]|Cell Movement/drug effects[MESH]|Glioma/*drug therapy/immunology/pathology[MESH]|Humans[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred BALB C[MESH]|Neoplasm Invasiveness[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Signal Transduction[MESH]|Transforming Growth Factor beta/antagonists & inhibitors[MESH]|Transforming Growth Factor beta1[MESH]|Transforming Growth Factor beta2[MESH] |
