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

Murugan Kalimutho, Antonella Minutolo, Sandro Grelli, Amanda Formosa, Giulia Sancesario, Alessandra Valentini, Giorgio Federici, Sergio Bernardini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1299-1312
Number of pages14
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number6
DOIs
Publication statusPublished - Jun 2011

Keywords

  • Apoptosis
  • CRC
  • miR-34a
  • Oxaliplatin
  • p53
  • Platinum
  • Satraplatin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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