title: Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
abstract: The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2-p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11-Rad50-Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53.
  
  
  CONCLUSIONS
  Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Alexia M
authors.initials: AM
authors.lastname: Carrillo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Mellissa
authors.initials: M
authors.lastname: Hicks
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Dineo
authors.initials: D
authors.lastname: Khabele
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. christine.eischen@vanderbilt.edu.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens; D010051:Ovarian Neoplasms / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D007093:Imidazoles; D009153:Mutagens; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D005047:Etoposide; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin