title: Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells.
abstract: BACKGROUND
  Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers. Despite recent advances in OSCC diagnostics and therapeutics, the overall survival rate still remains low. Here, we assessed the efficacy of a combinatorial arsenic trioxide (ATO) and cisplatin (CDDP) treatment in human OSCC cells.
  
  
  METHODS
  The combinatorial effect of ATO/CDDP on the growth and apoptosis of OSCC cell lines HSC-2, HSC-3, and HSC-4 was evaluated using MTT and annexin V assays, respectively. Chou-Talalay analyses were preformed to evaluate the combinatorial effects of ATO/CDDP on the dose-reduction index (DRI). To clarify the mechanism underlying the ATO/CDDP anticancer effect, we also examined the involvement of reactive oxygen species (ROS) in ATO/CDDP-induced apoptosis.
  
  
  RESULTS
  Combination index (CI) analyses revealed that a synergistic interaction of ATO and CDDP elicits a wide range of effects in HSC-2 cells, with CI values ranging from 0.78 to 0.90, where CI < 1 defines synergism. The CI values in HSC-3 and HSC-4 cells ranged from 0.34 to 0.45 and from 0.60 to 0.92, respectively. In addition, ATO/CDDP yielded favorable DRI values ranging from 1.6-fold to 7.71-fold dose reduction. Compared to mono-therapy, ATO/CDDP combinatorial therapy significantly augmented the loss of mitochondrial potential, caspase-3/7 activity and subsequent apoptosis. These changes were all abrogated by the antioxidant N-acetylcysteine.
  
  
  CONCLUSIONS
  This study provides the first evidence for a synergistic ATO/CDDP anticancer (apoptotic) activity in OSCC cells with a favorable DRI, thereby highlighting its potential as a combinational therapeutic regime in OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Nakaoka
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ono
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Akifumi
authors.initials: A
authors.lastname: Furuhashi
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Ohmura
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kazaoka
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D002945:Cisplatin; D000077237:Arsenic Trioxide