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Satraplatin (JM-216) mediates G2/M cell cycle arrest and potentiates apoptosis via multiple death pathways in colorectal cancer cells thus overcoming platinum chemo-resistance

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Abstract

Purposes

Satraplatin acts as a potent inhibitor of proliferation in castration-resistant prostate cancer, yet the basic and molecular pharmacological mechanisms are still unknown in all types of cancer including colorectal cancer (CRC). In an effort to explain the mechanism of tumour sensitivity to satraplatin, the cytotoxic effects in a panel of CRC cell lines was examined with regard to their p53 genotype in comparison with oxaliplatin.

Methods

CRC cell lines were chosen to ascertain the mechanism of satraplatin-enhanced cytotoxicity. Cells were incubated with oxaliplatin and satraplatin for 24–72 h, followed by the assessment of cell chemosensitivity with MTS. Western blot analysis was used to detect the expressions of p53-related molecules. Flow cytometry was used to monitor cell cycle perturbation while qRT-PCR to detect mRNA and miRNAs activities.

Results

Satraplatin treatment resulted an elevated increase in cell death in vitro compared to oxaliplatin preceded by an acute arrest at G2/M phase, along with cyclin B1 and p21waf/cip1 up-regulation. It also exhibited fourfold higher cellular platinum accumulations compared to oxaliplatin. Satraplatin treatment induces p53-related genes and its direct microRNA target of miR-34a independently. Thus, it potentiates apoptosis via multiple death pathways including the caspase 8 cleavages and Fas protein expression. The data suggest that the loss of p53 can increase oxaliplatin resistance but not satraplatin resistance.

Conclusion

Further molecular biology studies are needed to identify the activity of satraplatin in platinum-resistant cancer models and to determine whether this orally administered platinum analogue has synergistic effects in combination with other chemotherapy agents.

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Abbreviations

CRC:

Colorectal cancer

DISC:

Death-inducing signalling complex

miR:

MicroRNA

Satraplatin:

JM-216

IC:

Inhibitory concentration

CRPC:

Castration-resistant prostate cancer

UTR:

Untranslated region

Pt:

Platinum

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Acknowledgments

This work was supported by grants from University Hospital Tor Vergata and Department of Internal Medicine, University of Rome, “Tor Vergata”. We thank to Dr, Isabella Faraoni, University of Rome Tor Vergata, Dr. Soddu and Dr. Maurizio Franculli from Regina Cancer Institute, Rome, Italy, Dr. Rossana Supino from Instituto Nazionale Tumori, Milan, Italy and Prof. Bert Vogelstein from Ludwig Center at John Hopkins, USA for providing us the cell lines for our analysis. We also thank Agennix for providing us with satraplatin drug. Thanks to Letizia Franzo’ for her invaluable technical assistance in atomic absorbance spectrometry assay.

Conflict of interest

The authors stated that there are no conflicts of interest regarding the publication of this article.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy

    Murugan Kalimutho, Amanda Formosa, Giulia Sancesario, Alessandra Valentini, Giorgio Federici & Sergio Bernardini

  2. Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, Rome, Italy

    Antonella Minutolo & Sandro Grelli

  3. Department of Laboratory Medicine, “U.O.C. Clinical Microbiology”, University Hospital Tor Vergata, Rome, Italy

    Antonella Minutolo & Sandro Grelli

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  1. Murugan Kalimutho
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Correspondence to Murugan Kalimutho or Sergio Bernardini.

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Kalimutho, M., Minutolo, A., Grelli, S. et al. Satraplatin (JM-216) mediates G2/M cell cycle arrest and potentiates apoptosis via multiple death pathways in colorectal cancer cells thus overcoming platinum chemo-resistance. Cancer Chemother Pharmacol 67, 1299–1312 (2011). https://doi.org/10.1007/s00280-010-1428-4

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