Abstract
Aim:
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 G2/M phase. Increased p53 protein expression was observed in the p53 wild-type HCT116 and LoVo cells together with p21waf1/cip1 protein up-regulation. However, p21waf1/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-p21waf1/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 G2/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.
Conclusion:
Collectively, our data suggest that satraplatin induces apoptosis in CRC cells, which is preceded by cell cycle arrest at G2/M due to the effect of 14-3-3σ and in a p53-p21waf1/cip1–independent manner. Taken together, these findings highlight the potential use of satraplatin for CRC treatment.
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Acknowledgements
This work was supported by grants from the University Hospital Tor Vergata and the Department of Internal Medicine, University of Rome, “Tor Vergata”. Murugan KALIMUTHO was supported by the Pre-doctoral Scholarship for foreign students under the International Italian Government University scholarship. We thank to Dr Isabella FARAONI, University of Rome Tor Vergata, Dr Soddu and Dr Maurizio FRANCULLI from the Regina Elena Cancer Institute, Rome, Italy, Dr Rossana SUPINO from the Instituto Nazionale Tumori, Milan, Italy and Prof Bert VOGELSTEIN from the Ludwig Center at John Hopkins, USA for providing us with the cell lines used in analysis. We also thank Agennix for providing us with satraplatin.
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Supplementary tables are available at Acta Pharmacologica Sinica website of NPG.
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Supplementary Table 1
Cell cycle perturbation folowing different concentrations of satraplatin (XLS 22 kb)
Supplementary Table 2
qRT-PCR relative fold changed expression data for p53 signaling pathway related genes following satraplatin treatment at 48 hours (5 μM) (XLS 36 kb)
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Kalimutho, M., Minutolo, A., Grelli, S. et al. Platinum-(IV)-derivative satraplatin induced G2/M cell cycle perturbation via p53-p21waf1/cip1-independent pathway in human colorectal cancer cells. Acta Pharmacol Sin 32, 1387–1396 (2011). https://doi.org/10.1038/aps.2011.107
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DOI: https://doi.org/10.1038/aps.2011.107
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