title: Anti-tumor effects of perphenazine on canine lymphoma.
abstract: Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. Perphenazine (PPZ) is one of the phenothiazines and widely used as an antipsychotic drug. Recently, it is reported that PPZ directly binds with scaffolding subunit of PP2A complex and exerts anti-tumor effects on human T cell acute lymphoblastic leukemia. However, the effect of PPZ on canine lymphoma has not been studied. Here, we investigated the potential therapeutic role of PPZ and its molecular mechanism in canine T-cell lymphoma. In canine T-cell lymphoma cell lines, UL-1 and Ema, PPZ decreased cell survival in a dose-dependent manner. Increased caspase 3 activity and Annexin V positive cells suggested that PPZ induced apoptosis. PPZ dephosphorylated Akt, MEK1/2 and ERK1/2. Akt inhibitor, but not MEK1/2 inhibitor and ERK1/2 inhibitor, induced cell death, indicating the importance of Akt dephosphorylation for the anti-tumor effect of PPZ. Finally, we observed enhanced PP2A activity by PPZ treatment. The present results for the first time revealed that PPZ induced canine lymphoma cells apoptosis through Akt dephosphorylation via PP2A activation. Our study suggests the possible therapeutic application of phenothiazines for canine T-cell lymphoma.
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Tsuji
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Yabe
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.forename: Takuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000662:veterinary; D015151:Immunoblotting / Q000662:veterinary; D008223:Lymphoma / Q000188:drug therapy / Q000662:veterinary*; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000662:veterinary; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000187:drug effects / Q000378:metabolism; D010546:Perphenazine / Q000627:therapeutic use*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051058:Oncogene Protein v-akt; D054648:Protein Phosphatase 2; D010546:Perphenazine