Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells

被引：16

作者：

Arimany-Nardi, C. ^{[1
,2
]}

Montraveta, A. ^{[3
]}

Lee-Verges, E. ^{[3
]}

Puente, X. S. ^{[4
]}

Koepsell, H. ^{[5
]}

Campo, E. ^{[6
]}

Colomer, D. ^{[3
,6
]}

Pastor-Anglada, M. ^{[1
,2
]}

机构：

[1] Univ Barcelona, Dept Biochem & Mol Biol, Inst Biomed, E-08028 Barcelona, Spain

[2] Inst Salud Carlos III, Natl Biomed Res Inst Liver & Gastrointestinal Dis, Oncol Program, Madrid, Spain

[3] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Expt Therapeut Lymphoid Malignancies Grp, Barcelona, Spain

[4] Univ Oviedo, Inst Oncol, Oviedo, Spain

[5] Univ Wurzburg, Julius von Sachs Inst, Dept Mol Plant Physiol & Biophys, Wurzburg, Germany

[6] Hosp Clin IDIBAPS, Hematopathol Unit, Barcelona, Spain

来源：

PHARMACOGENOMICS JOURNAL | 2015年 / 15卷 / 04期

关键词：

IDENTIFIES RECURRENT MUTATIONS; PREVIOUSLY UNTREATED PATIENTS; DRUG UPTAKE TRANSPORTERS; PHASE-II TRIAL; OCT1; SLC22A1; EXPRESSION; FLUDARABINE; RITUXIMAB; COMBINATION; VARIANTS;

D O I：

10.1038/tpj.2014.77

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：363 / 371

页数：9

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