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PMID: 15967103 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers.

Neoplasia (New York, N.Y.) ·Vol. 7 ·No. 5 ·2005-05-00 ·Pages 509-21

Halder SK, Beauchamp RD, Datta PK

Abstract

Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-beta (TGF-beta) in advanced stage carcinogenesis provides a potentially interesting drug target for therapeutic intervention. Although very few TGF-beta receptor kinase inhibitors (TRKI) are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-beta, or when these inhibitors might be useful for treatment during cancer progression. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-beta-induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-beta, including TGF-beta-induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-beta, whereas it reduces colony formation by cells that are growth-promoted by TGF-beta. However, SB-431542 has no effect on a cell line that failed to respond to TGF-beta. This represents a novel potential application of these inhibitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-beta-induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-beta.

MeSH Terms
Activin Receptors, Type I/antagonists & inhibitors Animals Antineoplastic Agents/pharmacology Apoptosis Benzamides/pharmacology Blotting, Western Cell Adhesion Cell Line Cell Line, Tumor Cell Movement Dioxoles/pharmacology Enzyme Inhibitors/pharmacology Gene Expression Regulation, Neoplastic Humans Immunoprecipitation Mice Mink Models, Biological Neoplasm Invasiveness Neoplasm Metastasis Neovascularization, Pathologic Protein Serine-Threonine Kinases Rats Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta/antagonists & inhibitors Time Factors Transcription, Genetic Transforming Growth Factor beta/metabolism Vascular Endothelial Growth Factor A/metabolism
Chemicals
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide Antineoplastic Agents Benzamides Dioxoles Enzyme Inhibitors Receptors, Transforming Growth Factor beta Transforming Growth Factor beta Vascular Endothelial Growth Factor A Protein Serine-Threonine Kinases Activin Receptors, Type I Receptor, Transforming Growth Factor-beta Type I Tgfbr1 protein, rat
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Halder Sunil K
Department of Surgery and Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Beauchamp R Daniel
Datta Pran K
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Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1522-8002
DOI
10.1593/neo.04640
Published
2005-05-00
Pages
509-21
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC1501161
Subset
IM
Grants
NIDDK NIH HHS · R01 DK52334 · United States
NCI NIH HHS · R01 CA95195 · United States
NCI NIH HHS · 5P50CA90949 · United States
NCI NIH HHS · P50 CA090949 · United States
NCI NIH HHS · R01 CA069457 · United States
NIDDK NIH HHS · R01 DK052334 · United States
NCI NIH HHS · R01 CA095195 · United States
NCI NIH HHS · CA69457 · United States
External Links
PubMed source DOI: 10.1593/neo.04640 PMC Full Text
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