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LY2157299一水合物，一种转化生长因子-β受体1抑制剂，可抑制卵巢癌的肿瘤生长和腹水形成。

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer.

作者信息

Zhang Qing, Hou Xiaonan, Evans Bradley J, VanBlaricom Jamison L, Weroha Saravut J, Cliby William A

机构信息

Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USA.

Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.

出版信息

Cancers (Basel). 2018 Aug 7;10(8):260. doi: 10.3390/cancers10080260.

DOI:10.3390/cancers10080260
PMID:30087253
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6115954/
Abstract

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

摘要

转化生长因子β（TGF-β）信号传导具有多效性功能，可调节癌症的起始、发展和转移，并且在基质细胞与癌细胞之间的相互作用中也发挥重要作用，这使得该信号通路成为一个潜在的治疗靶点。对TGF-β受体I（TGFBRI）抑制剂一水合LY2157299（LY）在高级别浆液性卵巢癌（HGSOC）细胞系和异种移植模型中抑制卵巢癌（OC）生长的能力进行了研究。采用免疫组织化学、qRT-PCR和蛋白质印迹法研究LY处理对癌细胞和成纤维细胞衍生基因表达的影响。结果显示，在所有测试的OC细胞系中，暴露于TGF-β1均可诱导SMAD2和SMAD3磷酸化，但这种诱导作用可被LY预处理所抑制。单独使用LY可在体外抑制HGSOC细胞的增殖、迁移和侵袭。LY可阻断TGF-β1诱导的成纤维细胞活化。LY在体内还可延缓肿瘤生长并抑制腹水形成。此外，不依赖于肿瘤抑制作用，LY可在体内减少腹水形成。利用OVCAR8异种移植标本，我们证实了LY对TGF-β信号传导以及肿瘤基质中XI型胶原链1（COL11A1）和多功能蛋白聚糖（VCAN）表达的抑制作用。这些观察结果提示抗TGF-β信号传导定向治疗在卵巢癌中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/18f34dc1ecd2/cancers-10-00260-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/b6d151644ab5/cancers-10-00260-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/ad47024985b7/cancers-10-00260-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/abb95493c890/cancers-10-00260-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/4b330b08714f/cancers-10-00260-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/988e571b8765/cancers-10-00260-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/18f34dc1ecd2/cancers-10-00260-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/b6d151644ab5/cancers-10-00260-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/ad47024985b7/cancers-10-00260-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/abb95493c890/cancers-10-00260-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/4b330b08714f/cancers-10-00260-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/988e571b8765/cancers-10-00260-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ea3/6115954/18f34dc1ecd2/cancers-10-00260-g006.jpg

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