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

Cancer Sci. 2007 Jan;98(1):127-33. doi: 10.1111/j.1349-7006.2006.00357.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / drug effects
  • Activin Receptors, Type I / pharmacokinetics*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / secondary
  • Female
  • Humans
  • Immunoblotting
  • In Vitro Techniques
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / 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

Substances

  • 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