title: Arsenic sulfide induces apoptosis and autophagy through the activation of ROS/JNK and suppression of Akt/mTOR signaling pathways in osteosarcoma.
abstract: Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As2S2), 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 As2S2in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As2S2potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As2S2induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As2S2was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As2S2-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As2S2inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As2S2-induced apoptosis and autophagy. Finally, As2S2in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As2S2induced 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.
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: gangyang_wang@163.com.
authors.forename: Gangyang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zhangtaoabc@2008.sina.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: viv-sun@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: 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. Electronic address: wanghs1231@gmail.com.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yinfeicat@163.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wyz135@163.com.
authors.forename: Zhuoying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: zuozuo198@163.com.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Zuo
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: sunmengxiong@126.com.
authors.forename: Mengxiong
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Orthopaedics, Shanghai East Hospital, Tongji University, Shanghai, China. Electronic address: zhouzf@yeah.net.
authors.forename: Zifei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: nylbh7581@163.com.
authors.forename: Binhui
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: piao_hay@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: hua_yingqi@163.com.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: lihaoqing@medmail.com.
authors.forename: Haoqing
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: czd856@vip.163.com.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000008:administration & dosage*; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008516:Medicine, Chinese Traditional; D051379:Mice; D051058:Oncogene Protein v-akt / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013440:Sulfides / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; D017382:Reactive Oxygen Species; D013440:Sulfides; C045816:arsenic trisulfide; C058317:arsenic disulfide; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases
keywords: Apoptosis; Arsenic sulfide; Autophagy; Cell cycle; Osteosarcoma