Ki26894, a novel transforming growth factor-[beta] type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line.
Ehata, Shogo 1,2; Hanyu, Aki 1; Fujime, Makoto 2; Katsuno, Yoko 1,3; Fukunaga, Erina 1; Goto, Kouichiro 3; Ishikawa, Yuichi 4; Nomura, Kimie 4; Yokoo, Hiroshi 4; Shimizu, Toshiyuki 5; Ogata, Etsuro 6; Miyazono, Kohei 1,3; Shimizu, Kiyoshi 5; Imamura, Takeshi 1,7
[Article] Cancer Science. 98(1):127-133, January 2007.

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Transforming growth factor (TGF)-[beta] signaling has been shown to promote tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-[beta] signaling may thus be a novel strategy for treatment of patients with such cancers. In this study, we investigated the effects of a novel TGF-[beta] type I receptor (T[beta]R-I) kinase inhibitor, Ki26894, on bone metastasis of a highly bone-metastatic variant of human breast cancer MDA-MB-231 cells, termed MDA-MB-231-5a-D (MDA-231-D). Ki26894 blocked TGF-[beta] signaling in MDA-231-D cells, as detected by suppression of phosphorylation of Smad2 and inhibition of TGF-[beta]-responsive reporter activity. Moreover, Ki26894 decreased the motility and the invasion of MDA-231-D cells induced by TGF-[beta] in vitro. Ki26894 also suppressed transcription of plasminogen activator inhibitor-1 (PAI-1), parathyroid hormone-related protein (PTHrP), and interleukin-11 (IL-11) mRNA of MDA-231-D cells, which were stimulated by TGF-[beta]. X-ray radiography revealed that systemic Ki26894 treatment initiated 1 day before the inoculation of MDA-231-D cells into the left ventricle of BALB/c nu/nu female mice resulted in decreased bone metastasis of breast cancer cells. Moreover, Ki26894 prolonged the survival of mice inoculated with MDA-231-D cells compared to vehicle-treated mice. These findings suggest that T[beta]R-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.

Copyright (C) 2007 Blackwell Publishing Ltd.