title: Comparison of the antitumor effects of an MDM2 inhibitor, nutlin-3, in feline lymphoma cell lines with or without p53 mutation.
abstract: The P53 tumor suppressor protein is a multifunctional transcription factor that prevents the malignant transformation of normal cells. In human malignancies, p53 is the most frequently altered gene and is mutated in approximately 50% of all malignancies. In contrast, p53 gene mutation has been rarely detected in feline malignancies, and most feline malignancies conceivably retain the wild-type p53 (wt-p53) gene. MDM2 negatively regulates the P53 protein by inhibiting its transcriptional activity and nuclear transport and by inducing its degradation. Inhibition of P53-MDM2 interaction stabilizes P53 protein and activates P53 pathway. Nutlin-3, a small molecule that inhibits P53-MDM2 interaction, was shown to have an antitumor effect in several human cancer cells retaining the wt-p53 gene. In the present study, we evaluated and compared the antitumor effect of nutlin-3 in 5 different feline lymphoma cell lines, of which 3 harbored wt-p53, and 2, mutated p53 (mt-p53). Treatment with nutlin-3 resulted in increased amounts of P53 protein in conjunction with augmented expression of P53-target genes in 3 feline lymphoma cell lines with the wt-p53 gene, but not in 2 feline lymphoma cell lines with the mt-p53 gene. Nutlin-3 treatment also induced G1-S and/or G2-M cell cycle arrest and apoptosis in lymphoma cell lines with wt-p53. Nutlin-3 treatment induced cell cycle arrest but not apoptosis in the cell lines with mt-p53. From these results, we concluded that nutlin-3 has an antitumor effect on feline lymphoma cell lines harboring the wt-p53 gene through accumulation and activation of P53 leading to cell cycle arrest and apoptosis. The present study suggests that inhibition of P53-MDM2 interaction using nutlin-3 may be a new therapeutic strategy for treating feline lymphoma retaining the wt-p53 gene.
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Goto-Koshino
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujino
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohno
authors.forename: Hajime
authors.initials: H
authors.lastname: Tsujimoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002371:Cat Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002415:Cats; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2