The novel trinuclear platinum complex BBR3464 induces a cellular response different from cisplatin.
BBR3464 is a new platinum-based drug non cross-resistant with cisplatin. To characterise the cellular basis of BBR3464 cytotoxicity as opposed to cisplatin, we performed a comparative study of the two drugs in cisplatin-resistant neuroblastoma and astrocytoma cells. In both model systems, BBR3464 proved to be more potent than cisplatin and was able to overcome cisplatin resistance. The higher potency exhibited by BBR3464 correlated with an increased cellular platinum accumulation and DNA-adduct formation. At equitoxic doses, BBR3464 induced apoptosis to a lesser extent than cisplatin and failed to overcome the decreased susceptibility to cisplatin-induced apoptosis in cisplatin-resistant cells. Cell cycle analysis showed a dose-dependent G2/M arrest by BBR3464. In astrocytoma cells, cisplatin treatment resulted in the upregulation of p53, p21 and bax, while only p21 induction was observed after BBR3464 treatment. In cisplatin-resistant cells, the reduced sensitivity to cisplatin paralleled a resistance to the induction of p53/p21 pathway by cisplatin, while the same doses of BBR3464 induced p21 to a similar extent in the resistant cells as in the parental cells. In conclusion, BBR3464 induces a cellular response that is different from cisplatin, supporting the view that the two drugs act through different mechanisms. Our data indicate that BBR3464 may be a promising agent in the treatment of tumours unresponsive to cisplatin and with a non-functional p53.
Servidei
T
T
Department of Paediatrics, Division of Paediatric Oncology, Catholic University of Rome, Largo A. Gemelli, 8-00168, Rome, Italy.
Ferlini
C
C
Riccardi
A
A
Meco
D
D
Scambia
G
G
Segni
G
G
Manzotti
C
C
Riccardi
R
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; C494826:BAX protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020741:rho GTP-Binding Proteins; C114062:BBR 3464; D002945:Cisplatin