title: Platinum-(IV)-derivative satraplatin induced G2/M cell cycle perturbation via p53-p21(waf1/cip1)-independent pathway in human colorectal cancer cells.
abstract: OBJECTIVE
  Platinum-(IV)-derivative satraplatin represents a new generation of orally available anti-cancer drugs that are under development for the treatment of several cancers. Understanding the mechanisms of cell cycle modulation and apoptosis is necessary to define the mode of action of satraplatin. In this study, we investigate the ability of satraplatin to induce cell cycle perturbation, clonogenicity loss and apoptosis in colorectal cancer (CRC) cells.
  
  
  METHODS
  CRC cells were treated with satraplatin, and the effects of satraplatin on apoptosis and the cell cycle were evaluated by flow cytometry. Western blot analysis was used to investigate the effects of satraplatin on cell cycle and apoptosis-related proteins. RT-qPCR was used to evaluate p53-related mRNA modulation.
  
  
  RESULTS
  Satraplatin induced an accumulation of CRC cells predominantly in the G(2)/M phase. Increased p53 protein expression was observed in the p53 wild-type HCT116 and LoVo cells together with p21(waf1/cip1) protein up-regulation. However, p21(waf1/cip1) protein accumulation was not observed in the p53 mutant HCT15, HT29, and WiDr cells, even when p53 protein expression was compromised, suggesting that the cell cycle perturbation is p53-p21(waf1/cip1) independent. Following a candidate approach, we found an elevated expression of 14-3-3σ protein levels in CRC cells, which was independent of the status of p53, further supporting the role of satraplatin in the perturbation of the G(2)/M cell cycle phase. Moreover, satraplatin treatment induced apoptosis along with Bcl-2 protein down-regulation and abrogated the clonogenic formation of CRC cells in vitro.
  
  
  CONCLUSIONS
  Collectively, our data suggest that satraplatin induces apoptosis in CRC cells, which is preceded by cell cycle arrest at G(2)/M due to the effect of 14-3-3σ and in a p53-p21(waf1/cip1)-independent manner. Taken together, these findings highlight the potential use of satraplatin for CRC treatment.
authors.affiliation: Department of Internal Medicine, University of Rome "Tor Vergata", Italy. mceric_rugan@hotmail.com
authors.forename: Murugan
authors.initials: M
authors.lastname: Kalimutho
authors.forename: Antonella
authors.initials: A
authors.lastname: Minutolo
authors.forename: Sandro
authors.initials: S
authors.lastname: Grelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; C081294:satraplatin