Wang Gangyang, Zhang Tao, Sun Wei, Wang Hongsheng, Yin Fei, Wang Zhuoying, Zuo Dongqing, Sun Mengxiong, Zhou Zifei, Lin Binhui, Xu Jing, Hua Yingqi, Li Haoqing, Cai Zhengdong
Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.
Free Radic Biol Med. 2017 May;106:24-37. doi: 10.1016/j.freeradbiomed.2017.02.015. Epub 2017 Feb 7.
Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (AsS), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of AsS in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that AsS potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with AsS induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. AsS was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that AsS-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that AsS inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase AsS-induced apoptosis and autophagy. Finally, AsSin vivo suppressed tumor growth with few side effects. In summary, our results revealed that AsS induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma.
骨肉瘤是一种常见的原发性恶性骨肿瘤，在过去25至30年中其治愈率一直停滞不前。硫化砷（AsS）是中药雄黄的主要活性成分，已被证明在包括急性早幼粒细胞白血病、胃癌和结肠癌在内的多种肿瘤类型中具有抗肿瘤功效。在此，我们在体外和体内研究了AsS对骨肉瘤的疗效及作用机制。在本研究中，我们证明AsS通过诱导各种骨肉瘤细胞系的G2/M期阻滞来有效抑制细胞增殖。此外，AsS处理可诱导骨肉瘤细胞凋亡和自噬。凋亡诱导与PARP裂解以及caspase-3、-8、-9的激活有关。AsS被证明可诱导自噬，自噬体的形成和LC3II的积累证明了这一点。进一步研究表明，ROS清除剂和JNK抑制剂可显著减弱AsS诱导的凋亡和自噬。此外，我们发现AsS抑制Akt/mTOR信号通路，抑制Akt和mTOR激酶活性可增加AsS诱导的凋亡和自噬。最后，AsS在体内抑制肿瘤生长且副作用很少。总之，我们的结果表明，AsS通过激活ROS/JNK和阻断Akt/mTOR信号通路在人骨肉瘤细胞中诱导G2/M期阻滞、凋亡和自噬。硫化砷可能是一种潜在的针对骨肉瘤的临床抗肿瘤药物。
