双PI3K-BRD4抑制剂SF1126在体外和体内均抑制结肠癌细胞生长。
Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo.
作者信息
Qin An-Cheng, Li Ya, Zhou Li-Na, Xing Chun-Gen, Lu Xing-Sheng
机构信息
Department of Hepatobiliary Surgery, Suzhou Municipal Hospital affiliated to Nanjing Medical University, Suzhou, China.
The Central Lab, North District, Suzhou Municipal Hospital affiliated to Nanjing Medical University, Suzhou, China.
出版信息
Cell Physiol Biochem. 2019;52(4):758-768. doi: 10.33594/000000053.
BACKGROUND/AIMS: Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are key oncogenic cascades in colorectal cancer (CRC). SF1126 is a novel and potent PI3K-BRD4 dual inhibitor.
METHODS
CRC cells and human colon epithelial cells were treated with SF1126. Cell survival was tested by MTT and soft agar colony formation assays. Cell proliferation was tested by BrdU ELISA method. Cell apoptosis was tested by a TUNEL staining method and Histone DNA ELISA. Western blotting was utilized to test the signaling proteins. A HT-29 xenograft mice model was established to study the anti-tumor activity of SF1126 in vivo.
RESULTS
SF1126 potently inhibited the survival, proliferation, and progression of the cell cycle in an established CRC cell line (HT-29) and primary human colon cancer cells. Significant activation of apoptosis was detected in SF1126-treated CRC cells. In CRC cells, SF1126 blocked Akt-mammalian target of rapamycin (mTOR) complex1/2 signaling and downregulated BRD4 target proteins (Myc and cyclin D1). Further studies showed that SF1126 activated p38 signaling in CRC cells. In contrast, the p38 inhibitors or p38 short hairpin RNA inhibited SF1126-induced cytotoxicity and apoptosis in CRC cells. In vivo, subcutaneous administration of SF1126 significantly inhibited HT-29 xenograft tumor growth in nude mice.
CONCLUSION
SF1126 inhibits CRC cell growth possibly by targeting PI3K-Akt-mTOR, BRD4, and p38 signaling.
背景/目的：含溴结构域蛋白4（BRD4）和磷脂酰肌醇3激酶（PI3K）是结直肠癌（CRC）中的关键致癌级联反应。SF1126是一种新型强效PI3K-BRD4双重抑制剂。
方法
用SF1126处理CRC细胞和人结肠上皮细胞。通过MTT和软琼脂集落形成试验检测细胞存活情况。通过BrdU ELISA法检测细胞增殖。通过TUNEL染色法和组蛋白DNA ELISA检测细胞凋亡。利用蛋白质免疫印迹法检测信号蛋白。建立HT-29异种移植小鼠模型以研究SF1126在体内的抗肿瘤活性。
结果
SF1126有效抑制已建立的CRC细胞系（HT-29）和原发性人结肠癌细胞的存活、增殖及细胞周期进程。在经SF1126处理的CRC细胞中检测到明显的凋亡激活。在CRC细胞中，SF1126阻断Akt-雷帕霉素哺乳动物靶蛋白（mTOR）复合物1/2信号传导并下调BRD4靶蛋白（Myc和细胞周期蛋白D1）。进一步研究表明，SF1126激活CRC细胞中的p38信号传导。相反，p38抑制剂或p38短发夹RNA抑制SF1126诱导的CRC细胞毒性和凋亡。在体内，皮下注射SF1126可显著抑制裸鼠中HT-29异种移植瘤的生长。
结论
SF1126可能通过靶向PI3K-Akt-mTOR、BRD4和p38信号传导来抑制CRC细胞生长。
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