Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A.
The MDM2-antagonist Nutlin 3A can efficiently induce apoptosis in osteosarcoma cell lines with amplified MDM2. However, Nutlin-based therapy could be even more important in more common sarcoma types where this aberration is frequent. The well- and de-differentiated liposarcomas have complex marker chromosomes, consistently including multiple copies of the MDM2 locus. Since amplification seems to be a primary aberration in these tumors, whereas amplification in osteosarcoma generally is a progression marker, the underlying biological mechanisms may be different. We have therefore investigated the molecular response to Nutlin treatment in several liposarcoma cell lines with such markers, as well as a panel of other sarcoma cell lines. We report that Nutlin efficiently stabilized p53 and induced downstream p53 dependent transcription and apoptosis in liposarcoma cells with amplified MDM2 in vitro. Some effect of Nutlin was also observed on cell lines without amplified MDM2 but with wt TP53, but no apoptosis was induced. The MDM4 protein, reported to interfere with the reactivation of p53, was undetectable in cells with amplified MDM2. Thus, Nutlin represents a promising new therapeutic principle for the treatment of an increasing group of sarcomas.
Müller
Christoph R
CR
Department of Tumour Biology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Paulsen
Erik B
EB
Noordhuis
Paul
P
Pedeutour
Florence
F
Saeter
Gunnar
G
Myklebost
Ola
O
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008080:Liposarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2