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

The Pharmacogenomics Journal volume 15, pages 363–371 (2015)Cite this article

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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.

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Acknowledgements

We thank Ingrid Iglesias, Jocabed Roldan, Laura Jiménez and Sandra Cabezas for their technical support. We also thank all individuals with CLL who have participated in this study from the CLL Spanish Consortium. The UB laboratory is a member of the Oncology Program of the National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER ehd). CIBER ehd is an initiative of Instituto de Salud Carlos III (Spain). Part of this work was carried out at the Esther Koplowitz Center, Barcelona. This work has been funded by Mundipharma Research Ltd. This study was also partially supported by research funding from Ministerio de Ciencia e Innovación (SAF2011-23660 to MP-A. and SAF 12/31242 to DC), Redes Temáticas de Investigación Cooperativa de Cáncer from the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) ‘Una manera de hacer Europa’ RD12/0036/0004, RD12/0036/0036; RD12/0036/0067 and Generalitat de Catalunya 2009SGR967; 2014SGR346 (to DC) and 2009SGR624 (to MP-A). CAN, AM and EL are recipients of predoctoral fellowships FPI from Ministerio de Ciencia e Innovación.

Author Contributions

Cristina Arimany Nardi: wrote manuscript, designed research, performed research, analyzed data. Arnau Montraveta: wrote manuscript, performed research, analyzed data. Eriong Lee-Vergés: wrote manuscript, performed research, analyzed data. Xose S. Puente: wrote manuscript, contributed new reagents/analytical tools. Hermann Koepsell: reviewed manuscript, contributed new reagents/analytical tools. Elías Campo: reviewed manuscript. Dolors Colomer: wrote manuscript, designed research, analyzed data. Marçal Pastor-Anglada: wrote manuscript, designed research, analyzed data.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, Barcelona, Spain

    C Arimany-Nardi & M Pastor-Anglada

  2. Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER ehd), Instituto de Salud Carlos III, Madrid, Spain

    C Arimany-Nardi & M Pastor-Anglada

  3. Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    A Montraveta, E Lee-Vergés & D Colomer

  4. Institute of Oncology, University of Oviedo, Oviedo, Spain

    X S Puente

  5. Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs Insitute, University of Würzburg, Würzburg, Germany

    H Koepsell

  6. Hematopathology Unit, Hospital Clínic-IDIBAPS, Barcelona, Spain

    E Campo & D Colomer

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Correspondence to M Pastor-Anglada.

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This study was partially funded by Mundipharma.

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Arimany-Nardi, C., Montraveta, A., Lee-Vergés, E. et al. Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells. Pharmacogenomics J 15, 363–371 (2015). https://doi.org/10.1038/tpj.2014.77

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