期刊
DRUG DESIGN DEVELOPMENT AND THERAPY
卷 14, 期 -, 页码 745-755出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S203048
关键词
ESCC; radioresistance; JAK2; NVP-BSK805; DNA damage repair
资金
- National Natural Science Foundation of China [81672994]
- Zhejiang Provincial Natural Sciences Foundation of China [LZ15H220001, LY18H310012]
- Zhejiang Provincial Medical Scientific Research Foundation of China [2015PYA009]
- Hangzhou City Medical Scientific Research Foundation of Zhejiang Province, China [20180533B67]
- Hangzhou City Scientific Technology Research Foundation of Zhejiang Province, China [20150733Q63]
Purpose: Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo. Materials and Methods: Ninety-three kinase inhibitors were tested for their radiosensitizing effect in ESCC cells through high-content screening. The radiosensitizing effect of kinase inhibitors was investigated in vitro by detection of DNA double-strand breaks (DSBs) and clonogenic survival assay. By the establishment of xenograft tumor models in BALB/c nude mice, the radiosensitizing effect of kinase inhibitors was investigated in vivo. Results: Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase. After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo. JAK2 kinase was highly expressed in tumor tissues of ESCC patients, while rarely expressed in matched normal esophageal epithelial tissues. Survival analysis revealed JAK2 kinase as a prognostic factor of ESCC patients treated with chemoradiotherapy. Conclusion: Our study discovered JAK2 kinase as an attractive target to enhance the radiosensitivity of ESCC cells in vitro and in vivo.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据