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MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
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MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
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Journal Article
MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
2011
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,BMC
Subject
Antineoplastic Agents - pharmacology
/ Biomedical and Life Sciences
/ Cancer
/ Cell Proliferation - drug effects
/ Health Promotion and Disease Prevention
/ Humans
/ Oncology
/ Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
/ Proto-Oncogene Proteins c-mdm2 - genetics
/ Proto-Oncogene Proteins c-mdm2 - metabolism
/ Sarcoma
/ Signal Transduction - drug effects
/ Signal Transduction - genetics
