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.
OBJECTIVE
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 p21(waf/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.


CONCLUSIONS
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.
Kalimutho
Murugan
M
Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. mceric_rugan@hotmail.com
Minutolo
Antonella
A
Grelli
Sandro
S
Formosa
Amanda
A
Sancesario
Giulia
G
Valentini
Alessandra
A
Federici
Giorgio
G
Bernardini
Sergio
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; C081294:satraplatin