未折叠蛋白反应
Jurkat细胞
化学
内质网
癌细胞
癌症研究
癌症
肺癌
体内
白血病
药理学
免疫学
生物化学
生物
医学
病理
内科学
T细胞
免疫系统
生物技术
作者
Insa Klemt,Оleg А. Varzatskii,Roman A. Selin,Serhii Vakarov,Vladyslava Kovalska,Galyna Bila,Rostyslav Bilyy,Yan Z. Voloshin,Itziar Cossío Cuartero,Andrés Hidalgo,Benjamin Frey,Ina Becker,Bernhard Friedrich,Rainer Tietze,Ralf P. Friedrich,Christoph Alexiou,Elena-Laura Ursu,Alexandru Rotaru,Iris Solymosi,M. Eugenia Pérez‐Ojeda,Andriy Mokhir
摘要
The amount of unfolded proteins is increased in cancer cells, leading to endoplasmic reticulum (ER) stress. Therefore, cancer cells are sensitive to drugs capable of further enhancing ER stress. Examples of such drugs include the clinically approved proteosome inhibitors bortezomib and carfilzomib. Unfortunately, the known ER stress inducers exhibit dose-limiting side effects that justify the search for better, more cancer-specific drugs of this type. Herein, we report on FeC 2, which binds to unfolded proteins prevents their further processing, thereby leading to ER stress and ROS increase in cancer cells, but not in normal cells. FeC 2 exhibits low micromolar toxicity toward human acute promyelocytic leukemia HL-60, Burkitt's lymphoma BL-2, T-cell leukemia Jurkat, ovarian carcinoma A2780, lung cancer SK-MES-1, and murine lung cancer LLC1 cells. Due to the cancer-specific mode of action, 2 is not toxic in vivo up to the dose of 147 mg/kg, does not affect normal blood and bone marrow cells at the therapeutically active dose, but strongly suppresses both primary tumor growth (confirmed in Nemeth-Kellner lymphoma and LLC1 lung cancer models of murine tumor) and spreading of metastases (LLC1).
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