title: Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells.
abstract: Bendamustine is used in the treatment of chronic lymphocytic leukemia (CLL). Routes for bendamustine entry into target cells are unknown. This study aimed at identifying transporter proteins implicated in bendamustine uptake. Our results showed that hOCT1 is a bendamustine transporter, as bendamustine could cis-inhibit the uptake of a canonical hOCT1 substrate, with a Ki in the micromolar range, consistent with the EC50 values of the cytotoxicity triggered by this drug in HEK293 cells expressing hOCT1. hOCT1 polymorphic variants determining impaired bendamustine-transporter interaction, consistently reduced bendamustine cytotoxicity in HEK293 cells stably expressing them. Exome genotyping of the SLC22A1 gene, encoding hOCT1, was undertaken in a cohort of 241 CLL patients. Ex vivo cytotoxicity to bendamustine was measured in a subset of cases and shown to correlate with SLC22A1 polymorphic variants. In conclusion, hOCT1 is a suitable bendamustine transporter, thereby contributing to its cytotoxic effect depending upon the hOCT1 genetic variants expressed.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Barcelona, Spain [2] Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER ehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Arimany-Nardi
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Lee-Vergés
authors.affiliation: Institute of Oncology, University of Oviedo, Oviedo, Spain.
authors.forename: X S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs Insitute, University of Würzburg, Würzburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Koepsell
authors.affiliation: Hematopathology Unit, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.affiliation: 1] Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain [2] Hematopathology Unit, Hospital Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Colomer
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Barcelona, Spain [2] Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER ehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pastor-Anglada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069461:Bendamustine Hydrochloride / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D033721:Equilibrative Nucleoside Transporter 1; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; C491241:SLC22A12 protein, human; C065171:cif nucleoside transporter; D000069461:Bendamustine Hydrochloride