Therapeutic potential of Mdm2 inhibition in malignant germ cell tumours.
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.


METHODS
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.


METHODS
Biological consequences of Mdm2 inhibition were determined by analysis of the p53 pathway, cell proliferation, and apoptosis.


CONCLUSIONS
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.
Bauer
Sebastian
S
Sarcoma Centre, West German Cancer Centre, University Hospital Essen, Essen, Germany. sebastian.bauer@uni-due.de
Mühlenberg
Thomas
T
Leahy
Michael
M
Hoiczyk
Mathias
M
Gauler
Thomas
T
Schuler
Martin
M
Looijenga
Leendert
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018236:Carcinoma, Embryonal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin