title: Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy.
abstract: Ursolic acid (UA), a naturally occurring pentacyclic triterpene acid found in many medicinal herbs and edible plants, triggers apoptosis in several tumor cell lines but not in human bone cancer cells. Most recently, we have demonstrated that UA exposure reduces the viability of human osteosarcoma MG-63 cells through enhanced oxidative stress and apoptosis. Interestingly, an inhibitor of osteoclast-mediated bone resorption, zoledronic acid (ZOL), also a third-generation nitrogen-containing bisphosphonate, is effective in the treatment of bone metastases in patients with various solid tumors. In this present study, we found that UA combined with ZOL to significantly suppress cell viability, colony formation, and induce apoptosis in two lines of human osteosarcoma cells. The pre-treatment of the antioxidant had reversed the oxidative stress and cell viability inhibition in the combined treatment, indicating that oxidative stress is important in the combined anti-tumor effects. Moreover, we demonstrated that ZOL combined with UA significantly induced autophagy and co-administration of autophagy inhibitor reduces the growth inhibitory effect of combined treatment. Collectively, these data shed light on the pathways involved in the combined effects of ZOL and UA that might serve as a potential therapy against osteosarcoma.
authors.affiliation: Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan. 50560@cch.org.tw.|Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan. 50560@cch.org.tw.|Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung 40227, Taiwan. 50560@cch.org.tw.|School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. 50560@cch.org.tw.
authors.forename: Chia-Chieh
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan. 181064@cch.org.tw.
authors.forename: Yi-Fu
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan. 51114@cch.org.tw.|Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan. 51114@cch.org.tw.
authors.forename: Chen-Pu
authors.initials: CP
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung 40227, Taiwan. pjchueh@dragon.nchu.edu.tw.|Department of Biotechnology, Asia University, Taichung 41354, Taiwan. pjchueh@dragon.nchu.edu.tw.|Graduate Institute of Basic Medicine, China Medical University, Taichung 40402, Taiwan. pjchueh@dragon.nchu.edu.tw.|Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan. pjchueh@dragon.nchu.edu.tw.
authors.forename: Pin-Ju
authors.initials: PJ
authors.lastname: Chueh
authors.affiliation: School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. 31560@cch.org.tw.|Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua 50006, Taiwan. 31560@cch.org.tw.|Department of Surgery, Changhua Christian Hospital, 135 Nansiao St., Changhua 50006, Taiwan. 31560@cch.org.tw.
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000077211:Zoledronic Acid; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D017382:Reactive Oxygen Species; D014315:Triterpenes; D000077211:Zoledronic Acid; D000097245:Ursolic Acid
keywords: osteosarcoma; ursolic acid; zoledronic acid