title: Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors.
abstract: Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Minami
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Shinsato
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Homare
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Laboratory of Molecular Genetics, Institute of Frontier Medical Sciences, Jilin University, 1163 Xinmin Street, Changchun 130021, China.
authors.forename: Shaoxuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nishizawa
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Institute for Advanced Biosciences, Keio University, Mizukami 246-2, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Kohich
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Graduate School of Pharmaceutical Science, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0817, Japan.
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
authors.affiliation: Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Chijiiwa
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Huis Ten Bosch Cho 2825-7, Sasebo, Nagasaki 859-3298, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Clinical Research Center, National Kyushu Cancer Center, Notame, Minami-ku, Fukuoka 811-1395, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akiyama
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine and Oncology Programme, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD) Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pérez-Torras
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine and Oncology Programme, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD) Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Marcal
authors.initials: M
authors.lastname: Pastor-Anglada
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. Electronic address: furukawa@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Takeda
authors.initials: T
authors.lastname: Yasuo
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine
keywords: Anticancer agent resistance; Gemcitabine; Nucleoside transporter; Pancreatic cancer; Ribonucleotide reductase