title: Hypoxia-induced resistance to cisplatin-mediated apoptosis in osteosarcoma cells is reversed by gambogic acid independently of HIF-1α.
abstract: In vitro evidence of hypoxia-induced resistance to cisplatin (CDDP)-mediated apoptosis exists in human osteosarcoma (OS). Gambogic acid (GA) is a promising chemotherapeutic compound that could increase the chemotherapeutic effectiveness of CDDP in human OS cells by inducing cell cycle arrest and promoting apoptosis. This study examined whether GA could overcome OS cell resistance to CDDP. Hypoxia significantly reduced levels of CDDP-induced apoptosis in the OS cell lines MG63 and HOS. However, combined treatment with GA and CDDP revealed a strong synergistic action between these drugs, and higher protein levels of the apoptosis-related factor Fas, cleaved caspase-8 and cleaved caspase-3 and lower expression of hypoxia-inducible factor (HIF)-1α are detected in both cell lines. Meanwhile, drug resistance was not reversed by exposure to the HIF-1α inhibitor 2-methoxyestradiol. These findings strongly suggest that hypoxia-induced resistance to CDDP is reversed by GA in OS cells independently of HIF-1α. Furthermore, in vivo studies using xenograft mouse models revealed that combination therapy with CDDP and GA exerted increased antitumor effects by inducing apoptosis. Taken together, our results demonstrate that GA may be a new potent therapeutic agent useful for targeting human OS cells.
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China.
authors.forename: Shi-Qi
authors.initials: SQ
authors.lastname: Xia
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Zhuang
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China.
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China.
authors.forename: Chang-Cheng
authors.initials: CC
authors.lastname: You
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China. yanjinglong@hotmail.com.
authors.forename: Jing-Long
authors.initials: JL
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China. 30621708@qq.com.
authors.forename: Gong-Ping
authors.initials: GP
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D044004:Xanthones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D044004:Xanthones; C052659:gambogic acid; D002945:Cisplatin
keywords: Cisplatin; Gambogic acid; HIF-1α; Hypoxia; Osteosarcoma