title: Antitumor effect of a selective COX-2 inhibitor, celecoxib, may be attributed to angiogenesis inhibition through modulating the PTEN/PI3K/Akt/HIF-1 pathway in an H₂₂ murine hepatocarcinoma model.
abstract: Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been shown to affect the development of different types of cancer. The present study utilized a murine H22 hepatocarcinoma model to investigate the molecular mechanisms involved in celecoxib-induced inhibition of tumor angiogenesis. Tumor-bearing mice were randomly divided into five groups: i) control; ii) low-dose celecoxib (50 mg/kg); iii) high-dose celecoxib (200 mg/kg); iv) 5-fluorouracil (5-FU), (20 mg/kg) and v) combination of 5-FU and celecoxib (50 mg/kg). The antitumor effect of celecoxib was determined by measuring tumor volume. Tumor angiogenesis was evaluated by microvessel density (MVD). Tumor histology and immunostaining for CD34 in endothelial cells were performed to detect MVD. The expression levels of phosphatase and tensin homologue deleted from chromosome 10 (PTEN), phosphatidylinositol 3-kinase (PI3K), phospho‑Akt (P-Akt), COX-2, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) were detected by ELISA, immunohistochemistry and western blotting, respectively. We discovered substantial growth delay in murine H22 hepatoma as a result of celecoxib treatment. The inhibition rate of tumor growth induced by high-dose and low-dose celecoxib was 49.3 and 37.0%, respectively (P<0.05). The expression of PI3K, P-Akt, COX-2, HIF-1α, VEGF-A and PTEN in tumor tissues treated with celecoxib was demonstrated by immunohistochemistry, and the MVD was decreased in a dose-dependent manner (P<0.05). Reduced PI3K and P-Akt was particularly apparent in the high-dose celecoxib group (P<0.05). ELISA and western blotting data showed that the expression of PI3K, P-Akt, COX-2, HIF-1α and VEGF-A were reduced and PTEN was increased after treatment with celecoxib. In conclusion, the impact of celecoxib-induced tumor growth delay of murine H22 hepatocarcinoma may correlate with the inhibition of angiogenesis by reducing PI3K, P-Akt, COX-2, HIF-1α and VEGF-A expression and increasing PTEN expression in tumor tissue.
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Sui
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Yueying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Zhaopeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory for Modern Medicine and Technology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, P.R. China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D055806:Microvessels / Q000187:drug effects; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D052246:Cyclooxygenase 2 Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000068579:Celecoxib; D005472:Fluorouracil