Antitumour effect and modulation of expression of the ABCB1 gene by perifosine in canine lymphoid tumour cell lines

Hirotaka Tomiyasu, Yuko Goto-Koshino, Yasuhito Fujino, Koichi Ohno, Hajime Tsujimoto

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalVeterinary Journal
Volume201
Issue number1
DOIs
StatePublished - Jul 2014

Keywords

  • ABCB1
  • Akt
  • Canine
  • ERK
  • JNK
  • Lymphoma cell lines
  • Multidrug resistance
  • P-glycoprotein

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