title: Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel.
abstract: Tumor angiogenesis plays an important role in tumor progression and metastasis. Tumor endothelial cells (TECs) are a therapeutic target of antiangiogenic chemotherapy that was recently developed and is currently being investigated in the clinic with promising results. Low-dose chemotherapy, which is the long-term administration of relatively low doses of chemotherapeutic agents, has been proposed for targeting tumor angiogenesis in various types of cancers. Although the efficacy of low-dose chemotherapy has been confirmed in several clinical models, some studies show insufficient therapeutic effect for malignant cancers. As a possible mechanism of the treatment failure, it has been considered that tumor cells may acquire resistance to this therapy. However, drug resistance by TECs may also be due to another mechanism for resistance of tumor cells to low-dose chemotherapy. We reported elsewhere that TECs were resistant to the anticancer drug paclitaxel, which is a mitotic inhibitor, concomitant with P-glycoprotein up-regulation. Verapamil, a P-glycoprotein inhibitor, abrogated TEC resistance in vitro. Herein, we demonstrated that verapamil coadministration enhanced the effects of low-dose paclitaxel concomitant with inhibiting tumor angiogenesis in a preclinical in vivo mouse melanoma xenograft model. Furthermore, verapamil coadministration reduced lung metastasis. These results suggest that inhibiting P-glycoprotein in TECs may be a novel strategy for low-dose chemotherapy targeting TECs.
authors.affiliation: Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Nako
authors.initials: N
authors.lastname: Maishi
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.affiliation: Department of Cardiovascular and Thoracic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.affiliation: Department of Cell Physiology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan; Department of Oral Pathology and Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Mohammad Towfik
authors.initials: MT
authors.lastname: Alam
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ohmura
authors.affiliation: Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Chisaho
authors.initials: C
authors.lastname: Torii
authors.affiliation: Department of Oral Pathology and Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.affiliation: Division of Vascular Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Vascular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan. Electronic address: khida@igm.hokudai.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D059250:Administration, Metronomic; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000889:Anti-Arrhythmia Agents; D000972:Antineoplastic Agents, Phytogenic; D014700:Verapamil; D017239:Paclitaxel