Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo.

Abstract

PURPOSE:

Transforming growth factor-beta (TGF-beta) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-beta, they often constitutively overexpress and activate TGF-beta, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-beta pathway antagonists.

EXPERIMENTAL DESIGN:

We examined the effects of selective TGF-beta type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo.

RESULTS:

Both agents blocked TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-beta. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis.

CONCLUSION:

TGF-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.

• Authors: Rongrong Ge, Vaishali Rajeev, Partha Ray, Edmund Lattime, Susan Rittling, Satya Medicherla, Andy Protter, Alison Murphy, Jit Chakravarty, Sundeep Dugar, George Schreiner, Nicola Barnard, Michael Reiss
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 14 Pt 1 Pg. 4315-30 (Jul 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16857807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Plasminogen Activator Inhibitor 1
• Pteridines
• Receptors, Transforming Growth Factor beta
• SD-208
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma (drug therapy)
• Cell Proliferation
• Disease Progression
• Epithelium (pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitory Concentration 50
• Mammary Neoplasms, Animal (drug therapy)
• Mesoderm (pathology)
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Plasminogen Activator Inhibitor 1 (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pteridines (pharmacology)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta