title: All-trans retinoic acid enhances gemcitabine cytotoxicity in human pancreatic cancer cell line AsPC-1 by up-regulating protein expression of deoxycytidine kinase.
abstract: We previously showed that gemcitabine resistance in pancreatic cancer chemotherapy correlates with suppressed expression of deoxycytidine kinase (dCK), which catalyzes the rate-limiting step of gemcitabine activation. The purpose of the present study was to find a drug that might be useful to enhance the cytotoxicity of gemcitabine by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cell line AsPC-1. Screening of 40 prescription drugs identified 35 with no intrinsic cytotoxicity towards AsPC-1 cells. When AsPC-1 cells were pre-incubated with these drugs and then incubated with gemcitabine, we found that all-trans retinoic acid (ATRA) significantly decreased the viability by 28% compared with that of non-treated cells. Luciferase assay showed that ATRA transactivated the DCK promoter in AsPC-1 cells by about 2-fold compared with the untreated control, and an increase of dCK protein expression was confirmed by immunoblotting. ATRA decreased the half-maximal inhibitory concentration (IC50) of gemcitabine by 2.8-fold (ATRA-non-treated cells, 28.8nM; ATRA-treated cells, 10.0nM). The ATRA concentration of 0.03μM was sufficient to enhance gemcitabine cytotoxicity, and the effect was well maintained in the concentration range from 0.03 to 50μM. These results indicate that ATRA enhances gemcitabine cytotoxicity by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cells.
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Sendai 980-8578, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Sendai 980-8578, Japan. Electronic address: tachik-dds@umin.ac.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Sendai 980-8578, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aoba, Sendai 980-8575, Japan.
authors.forename: Koetsu
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aoba, Sendai 980-8575, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Ohtsuka
authors.affiliation: Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.affiliation: Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aoba, Sendai 980-8575, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aoba, Sendai 980-8578, Japan. Electronic address: terasaki.tetsuya@m.tohoku.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D014212:Tretinoin; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine
keywords: All-trans retinoic acid; Concomitant drug; Deoxycytidine kinase; Gemcitabine; Pancreatic cancer; Resistance