Cancer Biology Laboratory Institut Pasteur Korea Seongnam-si Korea.
Assay Development and Screening Institut Pasteur Korea Seongnam-si Korea.
FEBS Open Bio. 2018 Dec 6;9(1):82-91. doi: 10.1002/2211-5463.12552. eCollection 2019 Jan.
Radiation-induced pulmonary fibrosis (RIPF) triggers physiological abnormalities. Endothelial-to-mesenchymal transition (EndMT) is the phenotypic conversion of endothelial cells to fibroblast-like cells and is involved in RIPF. In this study, we established a phenomic screening platform to measure radiation-induced stress fibers and optimized the conditions for high-throughput screening using human umbilical vein endothelial cells (HUVECs) to develop compounds targeting RIPF. The results of screening indicated that CHIR-99021 reduced radiation-induced fibrosis, as evidenced by an enlargement of cell size and increases in actin stress fibers and α-smooth muscle actin expression. These effects were elicited without inducing serious toxicity in HUVECs, and the cytotoxic effect of ionizing radiation (IR) in nonsmall cell lung cancer was also enhanced. These results demonstrate that CHIR-99021 enhanced the effects of IR therapy by suppressing radiation-induced EndMT in lung cancer.
放射性肺纤维化（RIPF）引发生理异常。内皮-间充质转化（EndMT）是内皮细胞向成纤维细胞样细胞的表型转化，与 RIPF 有关。在这项研究中，我们建立了一个表型筛选平台来测量放射性诱导的应激纤维，并优化了使用人脐静脉内皮细胞（HUVEC）进行高通量筛选的条件，以开发针对 RIPF 的化合物。筛选结果表明，CHIR-99021 减少了放射性纤维化，表现为细胞大小增大，肌动蛋白应激纤维和α-平滑肌肌动蛋白表达增加。这些作用是在不诱导 HUVEC 严重毒性的情况下产生的，非小细胞肺癌中电离辐射（IR）的细胞毒性作用也增强了。这些结果表明，CHIR-99021 通过抑制肺癌中的放射性诱导的 EndMT 增强了 IR 治疗的效果。
