title: Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins.
abstract: OBJECTIVE
  Cisplatin (CDDP) is a platinum-based drug that is widely used in cancer chemotherapy, but the development of resistance in tumor cells is a major weakness of these treatments. Several mechanisms have been proposed to explain cisplatin resistance, and disruption of certain cellular pathways could modulate drug sensitivity to cisplatin. A lower level of cross-resistance to cisplatin leads to better outcomes in clinical use.
  
  
  METHODS
  Cross-resistance was assessed using cisplatin resistant lung cancer cell line A549/CDDP. Cell cycle analysis was used to examine the effect of cisplatin on cell signaling pathways regulating G2/M transition in cisplatin resistant cells.
  
  
  RESULTS
  A549/CDDP cells exhibited cross-resistance to carboplatin, but not oxaliplatin, which is often found in platinum analogues. Flow cytometry showed that nocodazole treatment caused a G2/M block in both A549/CDDP cells and cisplatin susceptible cells. However, A549/CDDP cells escaped the G2/M block following exposure to cisplatin. Activation of the Cdc2/CyclinB complex is required for transition from G2 to M phase, and the inactive form of phosphorylated Cdc2 is activated by Cdc25C dephosphorylation of Tyr15. In the cisplatin-treated susceptible cells, the levels of phosphorylated Cdc2 and Cdc25C were markedly decreased, leading to a loss of Cdc2 activity and G2/M arrest. In A549/CDDP cells, however, Cdc2 activity was supported by the expression of Cdc2 and Cdc25C after the addition of cisplatin, which resulted in G2/M progression.
  
  
  CONCLUSIONS
  The resistance phenotype of G2/M progression has been correlated with dysregulation of Cdc2 in a human lung cancer cell line selected for cisplatin.
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan; Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Sayo
authors.initials: S
authors.lastname: Horibe
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan. Electronic address: tana@kobepharma-u.ac.jp.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Tanahashi
authors.affiliation: Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawauchi
authors.affiliation: Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maegouchi
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yumoto
authors.affiliation: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Nagai
authors.affiliation: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Mikihisa
authors.initials: M
authors.lastname: Takano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D016195:G2 Phase / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints; D015739:Nocodazole / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin; D015739:Nocodazole
keywords: A549; Cdc2; Cdc25C; Cisplatin; Cross resistance; Drug resistance