title: Arsenic trioxide induces cervical cancer apoptosis, but specifically targets human papillomavirus-infected cell populations.
abstract: OBJECTIVE
  Human papillomavirus (HPV) is directly associated with the occurrence and development of cervical cancer. Targeting HPV infection has become the priority in treatment and prevention. Some treatment strategies have shown a limited therapeutic potential in suppressing and reversing the oncogenic effects of HPVs, but are compromised by the toxicity, immune suppression and the expense. Arsenic trioxide (As2O3) has shown therapeutic efficacy in the treatment of haematological and solid cancer and has been demonstrated to effectively induce apoptosis of HPV-infected cervical cancer cells in vitro. Here, we examined the effects and possible molecular pathway of As2O3-induced apoptosis in HPV-infected and noninfected cervical cancer cells.
  
  
  METHODS
  As2O3 was added to HPV-infected cell lines HeLa and CaSki and the HPV-negative cell line C33A at concentrations from 1 to 10 µmol/l. Cell proliferation rates were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays after exposure. Expressions of tumour suppressor gene p53, activated caspase-3 and cell cycle distribution were evaluated in relation to HPV-E6 protein expression by confocal microscopy immunofluorescent staining and flow cytometry.
  
  
  RESULTS
  As2O3 reduced cell populations by 16% in C33A but by 48-60% in HPV-infected cell lines CaSki and HeLa. The expression of HPV-E6 proteins was drastically down-regulated in a dose-dependent manner, whereas p53 and activated caspase-3 expressions increased in the HPV-infected cell lines. Flow cytometry demonstrated cell cycle arrest in S-G2/M phases, and increasing apoptotic bodies were seen in HPV-infected lines only.
  
  
  CONCLUSIONS
  As2O3, at low concentrations, inhibited HPV-E6 protein expression, leading to up-regulated p53 levels, induced S to G2/M arrest and apoptosis.
authors.affiliation: Centre for Investigative and Diagnostic Oncology, Middlesex University, London, UK.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Wen
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shiping
authors.initials: S
authors.lastname: Liu
authors.forename: Lucy
authors.initials: L
authors.lastname: Ghali
authors.forename: Ray K
authors.initials: RK
authors.lastname: Iles
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000821:virology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000821:virology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D010087:Oxides; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D000077237:Arsenic Trioxide