OSU-03012, a novel celecoxib derivative, induces reactive oxygen species-related autophagy in hepatocellular carcinoma
Journal
Cancer Research
Journal Volume
68
Journal Issue
22
Pages
9348-9357
Date Issued
2008
Author(s)
Gao M.
Yeh P.Y.
Chen K.-F.
Lee W.-C.
Feng W.-C.
Chen C.-S.
Kuo M.-L.
Abstract
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.
SDGs
Other Subjects
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
Type
journal article