title: MDM2 antagonism by nutlin-3 induces death in human medulloblastoma cells.
abstract: A critical component of the cellular stress response, the p53 tumor suppressor protein must be functional for many cancer therapies to be effective. Adjuvant therapies that augment p53 function are predicted to sensitize tumor cells to cancer therapies that rely upon p53 for their efficacy. Of those strategies currently being explored to enhance p53 function, inhibition of the ubiquitin ligase, MDM2, a negative regulator of p53, has shown promise. Here, we investigated whether MDM2 antagonism might be effective in inducing cell death in human medulloblastoma (MB) cells. Nutlin-3, a small-molecule inhibitor of MDM2, potently induced apoptosis in MB cells with wild-type TP53. Moreover, nutlin-3 potentiated p53 activation and growth impairment of MB cells in combination with the classic DNA-damaging agent doxorubicin. Together, these results support the concept that MDM2 antagonists may be therapeutically beneficial for patients with MB tumors.
authors.affiliation: Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ghassemifar
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mendrysa
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004396:Coloring Agents; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008527:Medulloblastoma / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D004396:Coloring Agents; D007093:Imidazoles; D010879:Piperazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C022616:thiazolyl blue