title: Nutlin-3 sensitizes nasopharyngeal carcinoma cells to cisplatin-induced cytotoxicity.
abstract: The small-molecule inhibitor of p53-Mdm2 interaction, Nutlin-3, is known to be effective against cancers expressing wild-type (wt) p53. p53 mutations are rare in nasopharyngeal carcinoma (NPC), hence targeting disruption of p53-Mdm2 interaction to reactivate p53 may offer a promising therapeutic strategy for NPC. In the present study, the effects of Nutlin-3 alone or in combination with cisplatin, a standard chemotherapeutic agent, were tested on C666-1 cells, an Epstein-Barr virus (EBV)-positive NPC cell line bearing wt p53. Treatment with Nutlin-3 activated the p53 pathway and sensitized NPC cells to the cytotoxic effects of cisplatin. The combined treatment also markedly suppressed soft agar colony growth formation and increased apoptosis of NPC cells. The effect of Nutlin-3 on NPC cells was inhibited by knockdown of p53, suggesting that its effect was p53-dependent. Extended treatment with increasing concentrations of Nutlin-3 did not result in emergence of p53 mutations in the C666-1 cells. Collectively, the present study revealed supportive evidence of the effectiveness of combining cisplatin and Nutlin-3 as a potential therapy against NPC.
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
authors.forename: Yee-Lin
authors.initials: YL
authors.lastname: Voon
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
authors.forename: Munirah
authors.initials: M
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Pooi-Fong
authors.initials: PF
authors.lastname: Wong
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
authors.forename: Roslina
authors.initials: R
authors.lastname: Husaini
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
authors.forename: Wayne Tiong-Weng
authors.initials: WT
authors.lastname: Ng
authors.affiliation: School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur 57000, Malaysia.
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
authors.affiliation: p53 Laboratory (p53Lab), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Republic of Singapore.
authors.forename: David Philip
authors.initials: DP
authors.lastname: Lane
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur 50588, Malaysia.
authors.forename: Alan Soo-Beng
authors.initials: AS
authors.lastname: Khoo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin