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.
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.
Ehata
Shogo
S
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo, Japan.
Hanyu
Aki
A
Fujime
Makoto
M
Katsuno
Yoko
Y
Fukunaga
Erina
E
Goto
Kouichiro
K
Ishikawa
Yuichi
Y
Nomura
Kimie
K
Yokoo
Hiroshi
H
Shimizu
Toshiyuki
T
Ogata
Etsuro
E
Miyazono
Kohei
K
Shimizu
Kiyoshi
K
Imamura
Takeshi
T
D030201:Activin Receptors, Type I / Q000187:drug effects / Q000493:pharmacokinetics* / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; C519257:Ki26894; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I