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.
机构:
Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Amada, Hideaki
Sekiguchi, Yoshinori
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Sekiguchi, Yoshinori
Ono, Naoya
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Ono, Naoya
Matsunaga, Yuko
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Matsunaga, Yuko
Koami, Takeshi
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Koami, Takeshi
Asanuma, Hajime
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Asanuma, Hajime
Shiozawa, Fumiyasu
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Shiozawa, Fumiyasu
Endo, Mayumi
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Endo, Mayumi
Ikeda, Akiko
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Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Ikeda, Akiko
Aoki, Mari
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Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Aoki, Mari
Fujimoto, Natsuko
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Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Fujimoto, Natsuko
Wada, Reiko
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Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
Wada, Reiko
Sato, Masakazu
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Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, JapanTaisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
机构:
Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Flevaris, Panagiotis
Khan, Sadiya S.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Khan, Sadiya S.
Eren, Mesut
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Eren, Mesut
Schuldt, Adam J. T.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Schuldt, Adam J. T.
Shah, Sanjiv J.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Shah, Sanjiv J.
Lee, Daniel C.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Lee, Daniel C.
Gupta, Sweta
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Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Gupta, Sweta
Shapiro, Amy D.
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Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Shapiro, Amy D.
Burridge, Paul W.
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Northwestern Univ, Feinberg Sch Med, Dept Pharmacol, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Burridge, Paul W.
Ghosh, Asish K.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Ghosh, Asish K.
Vaughan, Douglas E.
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Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA
Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USANorthwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA