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OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma

¹ Institute of Toxicology and ² Cancer Research Center, College of Medicine, National Taiwan University; Departments of ³ Oncology and ⁴ Internal Medicine and ⁵ National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan, Republic of China and ⁶ Division of Medical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio

Requests for reprints: Ann-Lii Cheng, Departments of Internal Medicine and Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan, Republic of China. Phone: 886-2-23123456, ext. 67251; Fax: 886-2-23711174; E-mail: alcheng{at}ntu.edu.tw or Min-Liang Kuo, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Ren-Ai Road, Taipei 10016, Taiwan, Republic of China. Phone: 886-2-23123456, ext. 88607; Fax: 886-2-23410217; E-mail: kuominliang{at}ntu.edu.tw.

Key Words: OSU-03012 • autophagy • hepatocellular carcinoma • reactive oxygen species

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. [Cancer Res 2008;68(22):9348–57]