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Research ArticleMetabolism, Transport, and Pharmacogenomics

Role of Equilibrative Nucleobase Transporter 1/SLC43A3 as a Ganciclovir Transporter in the Induction of Cytotoxic Effect of Ganciclovir in a Suicide Gene Therapy with Herpes Simplex Virus Thymidine Kinase

Junji Furukawa, Katsuhisa Inoue, Kinya Ohta, Tomoya Yasujima, Yoshihisa Mimura and Hiroaki Yuasa
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 59-68; DOI: https://doi.org/10.1124/jpet.116.236984
Junji Furukawa
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Katsuhisa Inoue
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Kinya Ohta
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Tomoya Yasujima
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Yoshihisa Mimura
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Hiroaki Yuasa
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (J.F., T.Y., Y.M., H.Y.); College of Pharmacy, Kinjo Gakuin University, Nagoya (K.O.); and Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan (K.I.)
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Abstract

A suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV) has been under development as a tumor-targeted therapy; however, the mechanism of cellular GCV uptake, which is prerequisite in the therapy, has not been clarified. In an attempt to resolve this situation and gain information to optimize HSV-TK/GCV system for cancer therapy, we found that human equilibrative nucleobase transporter 1 (ENBT1) can transport GCV with a Michaelis constant of 2.75 mM in Madin-Darby canine kidney II (MDCKII) cells stably transfected with this transporter. In subsequent experiments using green fluorescent protein (GFP)-tagged ENBT1 (GFP-ENBT1) and HSV-TK, the uptake of GCV (30 μM), which was minimal in MDCKII cells and unchanged by their transfection with HSV-TK alone, was increased extensively by their transfection with GFP-ENBT1, together with HSV-TK. Accordingly, cytotoxicity, which was assessed by the WST-8 cell viability assay after the treatment of those cells with GCV (30 μM) for 72 hours, was induced in those transfected with GFP-ENBT1, together with HSV-TK but not in those transfected with HSV-TK alone. These results suggest that ENBT1 could facilitate GCV uptake and thereby enhance cytotoxicity in HSV-TK/GCV system. We also identified Helacyton gartleri (HeLa) and HepG2 as cancer cell lines that are rich with ENBT1 and A549, HCT-15 and MCF-7 as those poor with ENBT1. Accordingly, the HSV-TK/GCV system was effective in inducing cytotoxicity in the former but not in the latter. Thus, ENBT1 was found to be a GCV transporter that could enhance the performance of HSV-TK/GCV suicide gene therapy.

Footnotes

    • Received August 3, 2016.
    • Accepted October 27, 2016.
  • This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (Grant 15K08082).

  • dx.doi.org/10.1124/jpet.116.236984.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Role of ENBT1 as a GCV Transporter in HSV-TK/GCV Therapy

Junji Furukawa, Katsuhisa Inoue, Kinya Ohta, Tomoya Yasujima, Yoshihisa Mimura and Hiroaki Yuasa
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 59-68; DOI: https://doi.org/10.1124/jpet.116.236984

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Role of ENBT1 as a GCV Transporter in HSV-TK/GCV Therapy

Junji Furukawa, Katsuhisa Inoue, Kinya Ohta, Tomoya Yasujima, Yoshihisa Mimura and Hiroaki Yuasa
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 59-68; DOI: https://doi.org/10.1124/jpet.116.236984
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