Open Access Highly Accessed Research article

MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines

Hege O Ohnstad1, Erik B Paulsen1, Paul Noordhuis1, Marianne Berg23, Ragnhild A Lothe23, Lyubomir T Vassilev4 and Ola Myklebost15*

Author Affiliations

1 Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, P O Box 4953 Nydalen, NO-0424 Oslo, Norway

2 Department of Cancer Prevention, The Norwegian Radium Hospital, Oslo University Hospital, P O Box 4953 Nydalen, NO-0424 Oslo, Norway

3 Center for Cancer Biomedicine, University of Oslo, 0316 Oslo, Norway

4 Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA

5 Institute for Molecular Bioscience, University of Oslo, 0316 Oslo, Norway

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BMC Cancer 2011, 11:211  doi:10.1186/1471-2407-11-211

Published: 30 May 2011

Abstract

Background

Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified MDM2 gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy.

Methods

A panel of sarcoma cell lines with different TP53 and MDM2 status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined.

Results

Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate.

Conclusion

The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.