An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer.
An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer.
复制标题
DOI：
--
复制
发表时间：
2009-06
影响因子：
2
通讯作者：
M. Rausch;T. Hahn;Lalitha V. Ramanathapuram;D. Bradley-Dunlop;D. Mahadevan;Melania E. Mercado-Pimentel;Raymond B. Runyan;D. Besselsen;Xiamei Zhang;H. Cheung;Wen-Cherng Lee;L. Ling;E. Akporiaye
中科院分区：
文献类型：
--
作者：
M. Rausch;T. Hahn;Lalitha V. Ramanathapuram;D. Bradley-Dunlop;D. Mahadevan;Melania E. Mercado-Pimentel;Raymond B. Runyan;D. Besselsen;Xiamei Zhang;H. Cheung;Wen-Cherng Lee;L. Ling;E. Akporiaye
背景转化生长因子β（TGF-β）在乳腺癌发生中起着复杂的作用。最初作为肿瘤抑制因子发挥作用，这种细胞因子后来通过增强恶性细胞的侵袭和转移潜力以及抑制抗肿瘤免疫而促进恶性细胞的进展。本研究的目的是研究SM 16（一种新型小分子ALK 5激酶抑制剂）治疗高转移性、产生TGF-β的小鼠乳腺癌（4 T1）的疗效。材料和方法用SM 16腹膜内（i. p.）或口服，并评估原发性和转移性肿瘤生长。结果SM 16可抑制体外培养的4 T1肿瘤细胞及4 T1肿瘤组织中Smad 2的磷酸化。SM 16阻断4 T1肿瘤细胞中TGF-β信号转导可防止TGF-β诱导的形态学变化，并抑制TGF-β诱导的体外侵袭。当通过每日腹膜内注射或通过小鼠食物口服递送时，SM 16抑制原发性和转移性4 T1肿瘤的生长。从SM 16饮食的小鼠分离的脾细胞显示增强的IFN-γ产生和抗肿瘤CTL活性。此外，SM 16未能抑制免疫缺陷SCID小鼠中已建立的4 T1肿瘤的生长和转移。结论SM 16的抗肿瘤作用依赖于免疫介导的机制，是治疗转移性乳腺癌的一种安全有效的药物。
BACKGROUND Transforming growth factor beta (TGF-beta) 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-beta-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-beta signal transduction in 4T1 tumor cells by SM16 prevented TGF-beta-induced morphological changes and inhibited TGF-beta-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-gamma 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.