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

Chia-Chieh Wu,Pin-Ju Chueh,Yi-Fu Huang,Yao-Li Chen,Chen-Pu Hsieh

doi:10.3390/molecules21121640

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.

Highlights

Osteosarcoma is known as osteogenic sarcoma which arises from osteoid tissue in the bone.This type of tumor most often localizes in the metaphysis of the adolescent long bones [1], which is characterized by a high propensity for metastasis, especially in lung
Cell viability was examined using MTT (3-(4,5-dimethylthiazol-2-y1)-2,5diphenyltetrazolium bromide) assay and we found that Ursolic acid (UA) significantly reduced cell viability at
These results clearly demonstrate that UA and zoledronic acid (ZOL), alone or in combination, significantly reduce osteosarcoma cell viability

Summary

Introduction

Osteosarcoma is known as osteogenic sarcoma which arises from osteoid tissue in the bone. This type of tumor most often localizes in the metaphysis of the adolescent long bones [1], which is characterized by a high propensity for metastasis, especially in lung. The outcome for this metastatic potential is frequently associated with high incidence of death in patients [2]. Molecules 2016, 21, 1640 for osteosarcoma include surgery, radiation therapy, chemotherapy and other new forms of treatments, such as immunotherapy and targeted therapy. Recent progress has focused on the chemoprevention by natural products for their anti-growth activity against cancer cells and may exhibit less side effects compared to synthetic compounds

Methods

Results

Conclusion