title: A novel approach to overcome multidrug resistance: utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors.
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.
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors: Yuta
authors: Y
authors: Yoshizawa
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors: Ken-ichi
authors: K
authors: Ogawara
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors: Toshikiro
authors: T
authors: Kimura
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: higaki@pharm.okayama-u.ac.jp.
authors: Kazutaka
authors: K
authors: Higaki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D008081:Liposomes; D008297:Male; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: Apoptosis; Liposome; P-glycoprotein; Paclitaxel; Vascular endothelial cells