title: OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues.
abstract: Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2'deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment.Cancer Res; 77(8); 2102-11. ©2017 AACR.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Drenberg
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Pounds
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Dena P
authors.initials: DP
authors.lastname: Rhinehart
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tübingen, Tübingen, Germany.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.affiliation: Division of Hematology, The Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Gruber
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio. baker.2480@osu.edu sparreboom.1@osu.edu.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio. baker.2480@osu.edu sparreboom.1@osu.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D002648:Child; D015331:Cohort Studies; D003412:Cricetulus; D003561:Cytarabine / Q000493:pharmacokinetics* / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D027981:Symporters; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; D027981:Symporters; D003561:Cytarabine; D003841:Deoxycytidine; D004176:Dipyridamole; D000093542:Gemcitabine