Ki26894, a novel transforming growth factor‐β type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line

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Abstract
Transforming growth factor (TGF)-β signaling has been shown to promote tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-β 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-β type I receptor (TβR-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-β signaling in MDA-231-D cells, as detected by suppression of phosphorylation of Smad2 and inhibition of TGF-β-responsive reporter activity. Moreover, Ki26894 decreased the motility and the invasion of MDA-231-D cells induced by TGF-βin 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-β. 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 TβR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers. (Cancer Sci 2007; 98: 127–133)