title: Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer.
abstract: BACKGROUND
  Dexamethasone (DEX) co-treatment has proved beneficial in NSCLC patients, improving clinical symptoms by the reduction of side effects after chemotherapy. However, recent studies have shown that DEX could render cancer cells more insensitive to cytotoxic drug therapy, but it is not known whether DEX co-treatment could influence therapy-induced senescence (TIS), and unknown whether it is in a p53-dependent or p53-independent manner.
  
  
  METHODS
  We examined in different human NSCLC cell lines and detected cellular senescence after cisplatin (DDP) treatment in the presence or absence of DEX. The in vivo effect of the combination of DEX and DDP was assessed by tumor growth experiments using human lung cancer cell lines growing as xenograft tumors in nude mice.
  
  
  RESULTS
  Co-treatment with DEX during chemotherapy in NSCLC resulted in increased tumor cell viability and inhibition of TIS compared with DDP treated group. DEX co-treatment cells exhibited the decrease of DNA damage signaling pathway proteins, the lower expression of p53 and p21(CIP1), the lower cellular secretory program and down-regulation of NF-κB and its signaling cascade. DEX also significantly reduced DDP sensitivity in vivo.
  
  
  CONCLUSIONS
  Our results underscore that DEX reduces chemotherapy sensitivity by blunting therapy induced cellular senescence after chemotherapy in NSCLC, which may, at least in part, in a p53-dependent manner. These data therefore raise concerns about the widespread combined use of gluocorticoids (GCs) with antineoplastic drugs in the clinical management of cancer patients.
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Ge
authors.forename: Songshi
authors.initials: S
authors.lastname: Ni
authors.forename: Xingan
authors.initials: X
authors.lastname: Wang
authors.forename: Nuo
authors.initials: N
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Dongli
authors.initials: D
authors.lastname: Song
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone; D002945:Cisplatin