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Molecules 2016, 21(12), 1640; doi:10.3390/molecules21121640

Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy

1,2,3,4
,
1
,
1,2
,
3,5,6,7,* and 4,8,9,*
1
Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan
2
Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan
3
Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung 40227, Taiwan
4
School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
5
Department of Biotechnology, Asia University, Taichung 41354, Taiwan
6
Graduate Institute of Basic Medicine, China Medical University, Taichung 40402, Taiwan
7
Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan
8
Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua 50006, Taiwan
9
Department of Surgery, Changhua Christian Hospital, 135 Nansiao St., Changhua 50006, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Maurizio Battino
Received: 25 October 2016 / Revised: 16 November 2016 / Accepted: 25 November 2016 / Published: 30 November 2016
View Full-Text   |   Download PDF [4681 KB, uploaded 30 November 2016]   |  

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. View Full-Text
Keywords: zoledronic acid; ursolic acid; osteosarcoma zoledronic acid; ursolic acid; osteosarcoma
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Wu, C.-C.; Huang, Y.-F.; Hsieh, C.-P.; Chueh, P.-J.; Chen, Y.-L. Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy. Molecules 2016, 21, 1640.

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