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.

Abstract

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 (TbetaR-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/cnu/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 TbetaR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.

• Authors: Shogo Ehata, Aki Hanyu, Makoto Fujime, Yoko Katsuno, Erina Fukunaga, Kouichiro Goto, Yuichi Ishikawa, Kimie Nomura, Hiroshi Yokoo, Toshiyuki Shimizu, Etsuro Ogata, Kohei Miyazono, Kiyoshi Shimizu, Takeshi Imamura
• Journal: Cancer science (Cancer Sci) Vol. 98 Issue 1 Pg. 127-33 (Jan 2007) ISSN: 1347-9032 [Print] England
• PMID: 17129361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ki26894
• Protein Kinase Inhibitors
• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Activin Receptors, Type I
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Activin Receptors, Type I (drug effects, pharmacokinetics)
• Animals
• Antineoplastic Agents (pharmacology)
• Bone Neoplasms (drug therapy, secondary)
• Female
• Humans
• Immunoblotting
• In Vitro Techniques
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Mice
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Metastasis (prevention & control)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction