TY - JOUR
T1 - Therapeutic potential of Mdm2 inhibition in malignant germ cell tumours
AU - Bauer, Sebastian
AU - Mühlenberg, Thomas
AU - Leahy, Michael
AU - Hoiczyk, Mathias
AU - Gauler, Thomas
AU - Schuler, Martin
AU - Looijenga, Leendert
N1 - Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2010/4
Y1 - 2010/4
N2 - BACKGROUND: Inadequate response to cisplatin-based chemotherapy is associated with poor prognosis in patients with advanced malignant testicular germ cell tumours (TGCTs), especially of the nonseminomatous type. Novel chemotherapeutic agents have failed so far to significantly improve the outcome of such patients. The majority of these tumours express low levels of p53, and TP53 mutations are rarely observed. Murine double minute 2 (Mdm2) inhibitors enhance apoptosis in tumours harbouring wild-type p53.OBJECTIVE: We sought to investigate the potential therapeutic value of Mdm2 in TGCT-derived cell lines with the histology of nonseminoma.DESIGN, SETTING, AND PARTICIPANTS: The Mdm2 inhibitor nutlin-3 was evaluated alone and in combination with cisplatin in a panel of germ cell tumour (GCT)-derived cell lines (embryonal carcinomas, being the nonseminomatous stem-cell component) with wild-type (NT2 and 2102EP cells) and mutant (NCCIT cells) p53 status.MEASUREMENTS: Biological consequences of Mdm2 inhibition were determined by analysis of the p53 pathway, cell proliferation, and apoptosis.RESULTS AND LIMITATIONS: Nutlin-3 exhibited significant activity (IC50 2.8 μM) in NT2 and 2102EP (wild-type p53) but not in p53-mutant NCCIT cells (<10% inhibition at 10 μM). At concentrations beyond 500 nM, additive effects were seen for the combination of nutlin-3 and cisplatin in NT2 and 2102EP cells but not in NCCIT cells. This correlated with the induction of p53 and its target p21, suggesting an on-target effect of nutlin-3. Moreover, nutlin-3 (5 μM) and cisplatin (0.5 μM) additively induced caspase cleavage and apoptosis in NT2 cells and 2102-EP cells but not in p53-mutant NCCIT cells.CONCLUSIONS: These results provide strong evidence for further development of pharmacologic Mdm2 inhibition for the treatment of patients suffering from high-risk nonseminomatous TGCT with wild-type p53 status.
AB - BACKGROUND: Inadequate response to cisplatin-based chemotherapy is associated with poor prognosis in patients with advanced malignant testicular germ cell tumours (TGCTs), especially of the nonseminomatous type. Novel chemotherapeutic agents have failed so far to significantly improve the outcome of such patients. The majority of these tumours express low levels of p53, and TP53 mutations are rarely observed. Murine double minute 2 (Mdm2) inhibitors enhance apoptosis in tumours harbouring wild-type p53.OBJECTIVE: We sought to investigate the potential therapeutic value of Mdm2 in TGCT-derived cell lines with the histology of nonseminoma.DESIGN, SETTING, AND PARTICIPANTS: The Mdm2 inhibitor nutlin-3 was evaluated alone and in combination with cisplatin in a panel of germ cell tumour (GCT)-derived cell lines (embryonal carcinomas, being the nonseminomatous stem-cell component) with wild-type (NT2 and 2102EP cells) and mutant (NCCIT cells) p53 status.MEASUREMENTS: Biological consequences of Mdm2 inhibition were determined by analysis of the p53 pathway, cell proliferation, and apoptosis.RESULTS AND LIMITATIONS: Nutlin-3 exhibited significant activity (IC50 2.8 μM) in NT2 and 2102EP (wild-type p53) but not in p53-mutant NCCIT cells (<10% inhibition at 10 μM). At concentrations beyond 500 nM, additive effects were seen for the combination of nutlin-3 and cisplatin in NT2 and 2102EP cells but not in NCCIT cells. This correlated with the induction of p53 and its target p21, suggesting an on-target effect of nutlin-3. Moreover, nutlin-3 (5 μM) and cisplatin (0.5 μM) additively induced caspase cleavage and apoptosis in NT2 cells and 2102-EP cells but not in p53-mutant NCCIT cells.CONCLUSIONS: These results provide strong evidence for further development of pharmacologic Mdm2 inhibition for the treatment of patients suffering from high-risk nonseminomatous TGCT with wild-type p53 status.
KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology
KW - Apoptosis/drug effects
KW - Carcinoma, Embryonal/enzymology
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cell Survival/drug effects
KW - Cisplatin/pharmacology
KW - Cyclin-Dependent Kinase Inhibitor p21/metabolism
KW - Dose-Response Relationship, Drug
KW - Drug Resistance, Neoplasm
KW - Enzyme Inhibitors/pharmacology
KW - Humans
KW - Imidazoles/pharmacology
KW - Inhibitory Concentration 50
KW - Male
KW - Mutation
KW - Piperazines/pharmacology
KW - Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors
KW - Testicular Neoplasms/enzymology
KW - Tumor Suppressor Protein p53/genetics
U2 - 10.1016/j.eururo.2009.06.014
DO - 10.1016/j.eururo.2009.06.014
M3 - Article
C2 - 19560254
SN - 0302-2838
VL - 57
SP - 679
EP - 687
JO - European Urology
JF - European Urology
IS - 4
ER -