title: Antitumour effect and modulation of expression of the ABCB1 gene by perifosine in canine lymphoid tumour cell lines.
abstract: Acquisition of multidrug resistance (MDR) is a common cause of treatment failure during chemotherapy for dogs with lymphoma (lymphosarcoma). Overexpression of P-glycoprotein (P-gp), encoded by the ABCB1 gene, is associated with MDR. Perifosine, an Akt inhibitor, downregulates the expression of P-gp. In this study, the antitumour effect of perifosine and its ability to modulate ABCB1 expression were examined in four canine lymphoid tumour cell lines (GL-1, CLBL-1, UL-1 and Ema). GL-1 and CLBL-1 were inherently negative for P-gp, while UL-1 and Ema were inherently positive for P-gp. GL-1 and UL-1 were sensitive to perifosine, whereas CLBL-1 and Ema were resistant. The amount of ABCB1 mRNA significantly decreased after treatment with perifosine in UL-1, associated with activation of the c-Jun NH2-terminal kinase (JNK) pathway, but such an effect was not observed in Ema. In UL-1, perifosine decreased the efflux of rhodamine 123 dye and reduced the 50% inhibitory concentration of vincristine, but such effects were not observed in Ema. Perifosine had an antitumour effect in 2/4 canine lymphoid tumour cell lines. In 1/4 cell lines, perifosine downregulated ABCB1 gene expression through activation of the JNK pathway and increased sensitivity to vincristine.
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tomiyasu
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Goto-Koshino
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujino
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. Electronic address: atsuji@mail.ecc.u-tokyo.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Tsujimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics* / Q000378:metabolism; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010767:Phosphorylcholine; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C105905:perifosine
keywords: ABCB1; Akt; Canine; ERK; JNK; Lymphoma cell lines; Multidrug resistance; P-glycoprotein