An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer

Matthew P. Rausch, Tobias Hahn, Lalitha Ramanathapuram, Deborah Bradley-Dunlop, Daruka Mahadevan, Melania Mercado-Pimentel, Raymond B Runyan, David G. Besselsen, Xiamei Zhang, H. Kam Cheung, Wen Cherng Lee, Leona E. Ling, Emmanuel T. Akporiaye

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Background: Transforming growth factor β (TGF-β) plays a complex role in breast carcinogenesis. Initially functioning as a tumor suppressor, this cytokine later contributes to the progression of malignant cells by enhancing their invasive and metastatic potential as well as suppressing antitumor immunity. The purpose of this study was to investigate the efficacy of SM16, a novel small molecule ALK5 kinase inhibitor, to treat a highly metastatic, TGF-β-producing murine mammary carcinoma (4T1). Materials and Methods: Mice bearing established 4T1 tumors were treated with SM16 intraperitoneally (i.p.) or orally, and primary and metastatic tumor growth was assessed. Results: SM16 inhibited Smad2 phosphorylation in cultured 4T1 tumor cells as well as primary and metastatic 4T1 tumor tissue. Blockade of TGF-β signal transduction in 4T1 tumor cells by SM16 prevented TGF-β-induced morphological changes and inhibited TGF-β-induced invasion in vitro. When delivered via daily i.p. injection or orally through mouse chow, SM16 inhibited the growth of primary and metastatic 4T1 tumors. Splenocytes isolated from mice on the SM16 diet displayed enhanced IFN-γ production and antitumor CTL activity. Furthermore, SM16 failed to inhibit the growth and metastasis of established 4T1 tumors in immunodeficient SCID mice. Conclusion: Taken together, the data indicate that the antitumor efficacy of SM16 is dependent on an immune-mediated mechanism and that SM16 may represent a safe and effective treatment for metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)2099-2109
Number of pages11
JournalAnticancer Research
Volume29
Issue number6
StatePublished - Jun 2009

Fingerprint

Growth Factor Receptors
Transforming Growth Factors
Breast Neoplasms
Growth
Neoplasms
Cultured Tumor Cells
SCID Mice
Immunity
Signal Transduction
Carcinogenesis
Breast
Phosphotransferases
Phosphorylation
Cytokines
Neoplasm Metastasis
Diet
Injections

Keywords

  • 4T1
  • Breast cancer
  • SM16
  • Small molecule TGFβRI/ALK5 kinase inhibitor
  • TGF-β

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Rausch, M. P., Hahn, T., Ramanathapuram, L., Bradley-Dunlop, D., Mahadevan, D., Mercado-Pimentel, M., ... Akporiaye, E. T. (2009). An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer. Anticancer Research, 29(6), 2099-2109.

An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer. / Rausch, Matthew P.; Hahn, Tobias; Ramanathapuram, Lalitha; Bradley-Dunlop, Deborah; Mahadevan, Daruka; Mercado-Pimentel, Melania; Runyan, Raymond B; Besselsen, David G.; Zhang, Xiamei; Cheung, H. Kam; Lee, Wen Cherng; Ling, Leona E.; Akporiaye, Emmanuel T.

In: Anticancer Research, Vol. 29, No. 6, 06.2009, p. 2099-2109.

Research output: Contribution to journalArticle

Rausch, MP, Hahn, T, Ramanathapuram, L, Bradley-Dunlop, D, Mahadevan, D, Mercado-Pimentel, M, Runyan, RB, Besselsen, DG, Zhang, X, Cheung, HK, Lee, WC, Ling, LE & Akporiaye, ET 2009, 'An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer', Anticancer Research, vol. 29, no. 6, pp. 2099-2109.
Rausch MP, Hahn T, Ramanathapuram L, Bradley-Dunlop D, Mahadevan D, Mercado-Pimentel M et al. An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer. Anticancer Research. 2009 Jun;29(6):2099-2109.
Rausch, Matthew P. ; Hahn, Tobias ; Ramanathapuram, Lalitha ; Bradley-Dunlop, Deborah ; Mahadevan, Daruka ; Mercado-Pimentel, Melania ; Runyan, Raymond B ; Besselsen, David G. ; Zhang, Xiamei ; Cheung, H. Kam ; Lee, Wen Cherng ; Ling, Leona E. ; Akporiaye, Emmanuel T. / An orally active small molecule TGF-β receptor I antagonist inhibits the growth of metastatic murine breast cancer. In: Anticancer Research. 2009 ; Vol. 29, No. 6. pp. 2099-2109.
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AU - Runyan, Raymond B

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AU - Akporiaye, Emmanuel T.

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