https://scholars.lib.ntu.edu.tw/handle/123456789/487336
標題: | OSU-03012, a novel celecoxib derivative, induces reactive oxygen species-related autophagy in hepatocellular carcinoma | 作者: | Gao M. Yeh P.Y. YEN-SHEN LU CHIH-HUNG HSU Chen K.-F. Lee W.-C. Feng W.-C. Chen C.-S. Kuo M.-L. ANN-LII CHENG |
公開日期: | 2008 | 卷: | 68 | 期: | 22 | 起(迄)頁: | 9348-9357 | 來源出版物: | Cancer Research | 摘要: | Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Systemic treatments for HCC have been largely unsuccessful. OSU-03012 is a derivative of celecoxib with anticancer activity. The mechanism of action is presumably 3-phosphoinositide- dependent kinase 1 (PDK1) inhibition. This study investigated the potential of OSU-03012 as a treatment for HCC. OSU-03012 inhibited cell growth of Huh7, Hep3B, and HepG2 cells with IC50 below 1 μmol/L. In Huh7 cells, OSU-03012 did not suppress PDK1 or AKT activity. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and flow cytometry analysis indicated that OSU-03012 did not induce cellular apoptosis. Instead, morphologic studies by light and electron microscopy, as well as special biological staining with monodansylcadaverine, acridine orange, and microtubule-associated protein 1 light chain 3, revealed OSU-03012-induced autophagy of Huh7 cells. This OSU-03012-induced autophagy was inhibited by 3-methyladenine. Moreover, reactive oxygen species (ROS) accumulation was detected after OSU-03012 treatment. Blocking ROS accumulation with ROS scavengers inhibited autophagy formation, indicating that ROS accumulation and subsequent autophagy formation might be a major mechanism of action of OSU-03012. Daily oral treatment of BALB/c nude mice with OSU-03012 suppressed the growth of Huh7 tumor xenografts. Electron microscopic observation indicated that OSU-03012 induced autophagy in vivo. Together, our results show that OSU-03012 induces autophagic cell death but not apoptosis in HCC and that the autophagy-inducing activity is at least partially related to ROS accumulation. ?2008 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-56449127196&doi=10.1158%2f0008-5472.CAN-08-1642&partnerID=40&md5=8ae4fcf07e034c81114769dc3058d9cc https://scholars.lib.ntu.edu.tw/handle/123456789/487336 |
ISSN: | 0008-5472 | DOI: | 10.1158/0008-5472.CAN-08-1642 | SDG/關鍵字: | acridine orange; celecoxib; dansylcadaverine; microtubule associated protein 1; osu 03012; reactive oxygen metabolite; unclassified drug; animal experiment; animal model; article; autophagy; cancer cell culture; controlled study; electron microscopy; enzyme activity; flow cytometry; human; human cell; liver cell carcinoma; male; microscopy; mouse; nick end labeling; nonhuman; nude mouse; priority journal; tumor xenograft; Adenine; Animals; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Pyrazoles; Reactive Oxygen Species; Sulfonamides; Xenograft Model Antitumor Assays |
顯示於: | 腫瘤醫學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。