title: XI-011 enhances cisplatin-induced apoptosis by functional restoration of p53 in head and neck cancer.
abstract: Head and neck cancer (HNC), one of the most common cancers worldwide, frequently involves mutation of the TP53 gene and dysregulation of the p53 pathway. Overexpression of MDM2 or MDM4 inactivates the tumor-suppressive function of p53. Restoration of p53 function that counteracts these p53 repressors can lead to in vivo tumor regression. Therefore, the present study assessed the ability of the small molecule p53 activator XI-011 (NSC146109) to induce apoptosis in HNC by restoring p53 function. We tested the effects of XI-011 treatment in HNC cell lines, either individually or in combination with cisplatin and assessed growth suppression, cell cycle arrest, and apoptosis. The drug effects on in vivo growth of HNC cells were examined in mice xenograft model. XI-011 exerted the highest growth suppression in tumor cells that overexpress MDM4, in which p53 is degraded. XI-011 treatment downregulated MDM4 mRNA and protein levels, and upregulated expression of proapoptotic genes and promoted apoptosis, in a dose-dependent manner. The apoptotic response was blocked by inhibition of p53 or expression of MDM4, demonstrating that the effects of XI-011 depend on p53 and MDM4. In combination treatments, XI-011 acted synergistically with cisplatin to inhibit growth of HNC cells in vitro and in vivo. MDM4 inhibition and functional restoration of p53 by XI-011 effectively enhanced cisplatin-induced cytotoxicity in HNC cells, an activity that suggests a promising strategy for treating HNC.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea, jonglyel.roh@gmail.com.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C568282:(10-methyl-9-anthryl)methyl imidothiocarbamate; D000873:Anthracenes; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D013890:Thiourea; D002945:Cisplatin