title: Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo.
abstract: OBJECTIVE
  Cervical cancer is the third most common type of cancer in women worldwide and radiotherapy remains its predominant therapeutic treatment. Artesunate (ART), a derivative of artemisinin, has shown radiosensitization effect in previous studies. However, such effects of ART have not yet been revealed for cervical cancer cells.
  
  
  METHODS
  The effect of ART on radiosensitivity of human cervical cancer cell lines HeLa and SiHa was assessed using the clonogenic assay. Cell cycle progression and apoptosis alterations were analyzed by flow cytometry. For in vivo study, HeLa or SiHa cells were inoculated into nude mice to establish tumors. Tissues from xenografts were obtained to detect the changes of microvessel density, apoptosis and cell cycle distribution. Microarray was used to analyze differentially expressed genes.
  
  
  RESULTS
  ART increased the radiosensitivity of HeLa cells (SER=1.43, P<0.001) but not of SiHa cells. Apoptosis and the G2-M phase transition induced by X-ray irradiation (IR) were enhanced by ART via increased Cyclin B1 expression in HeLa cells. Tumor growth of xenografts from HeLa but not SiHa cells was significantly inhibited by irradiation combined with ART (tumor volume reduction of 72.34% in IR+ART group vs. 41.22% in IR group in HeLa cells and 48.79% in IR+ART group vs. 44.03% in IR alone group in SiHa cells). Compared with the irradiated group, cell apoptosis was increased and the G2/M cell cycle arrest was enhanced in the group receiving irradiation combined with ART. Furthermore, compared with radiation alone, X-ray irradiation plus ART affected the expression of 203 genes that function in multiple pathways including RNA transport, the spliceosome, RNA degradation and p53 signaling.
  
  
  CONCLUSIONS
  ART potently abrogates the G2 checkpoint control in HeLa cells. ART can induce radiosensitivity of HeLa cells in vitro and in vivo.
authors.forename: Judong
authors.initials: J
authors.lastname: Luo
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Yiting
authors.initials: Y
authors.lastname: Tang
authors.forename: Han
authors.initials: H
authors.lastname: Cao
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rong
authors.initials: R
authors.lastname: Ji
authors.forename: Xifa
authors.initials: X
authors.lastname: Zhou
authors.forename: Zhongkai
authors.initials: Z
authors.lastname: Lu
authors.forename: Hongying
authors.initials: H
authors.lastname: Yang
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China. jpcao@suda.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D002277:Carcinoma / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D037621:Artemisinins; D011838:Radiation-Sensitizing Agents; D000077332:Artesunate; C031327:artemisinin