A novel approach to overcome multidrug resistance: Utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors

Yuta Yoshizawa, Ken Ichi Ogawara, Toshikiro Kimura, Kazutaka Higaki

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We tried to overcome the paclitaxel (PTX) resistance of cancer cells due to P-glycoprotein (P-gp) overexpression in the in vivo anti-tumor chemotherapy by utilizing polyethylene glycol-modified liposomal paclitaxel (PL-PTX). First of all, established were PTX-resistant Colon-26 cancer cells (C26/PTX) overexpressing P-gp, which provided IC50 value of PTX solution about 30 times larger than that obtained for control C26 (C26/control) in the in vitro MTT assay. Western blot analysis confirmed P-gp expression in C26/PTX 10 times higher than that in C26/control, indicating that the resistance acquisition of C26/PTX to PTX would be ascribed to the enhanced efflux of PTX by P-gp overexpressed in C26/PTX. However, the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice was similar to that in C26/control-bearing mice. Double immunohistochemical staining of vascular endothelial cells and apoptotic cells within tumor tissues demonstrated that the apoptotic cell death was preferentially observed in vascular endothelial cells in C26/PTX tumors after intravenous administration of PL-PTX, while that was in tumor cells in C26/control tumors. These results suggest that the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice would be ascribed to the cytotoxic action of PTX pumped out of tumor cells by overexpressed P-gp to vascular endothelial cells in tumor tissues.

Original languageEnglish
Pages (from-to)274-280
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Volume62
DOIs
Publication statusPublished - Oct 1 2014

Keywords

  • Apoptosis
  • Liposome
  • P-glycoprotein
  • Paclitaxel
  • Vascular endothelial cells

ASJC Scopus subject areas

  • Pharmaceutical Science

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