title: Renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake.
abstract: Chronic lymphatic leukemia (CLL) is often associated with nephritic syndrome. Effective treatment of CLL by chlorambucil and bendamustine leads to the restoration of renal function. In this contribution, we sought to elucidate the impact of organic anion transporters (OATs) on the uptake of bendamustine and chlorambucil as a probable reason for the superior efficacy of bendamustine over chlorambucil in the treatment of CLL. We examined the effects of structural analogs of p-aminohippurate (PAH), melphalan, chlorambucil, and bendamustine, on OAT1-mediated [(3)H]PAH uptake and OAT3- and OAT4-mediated [(3)H]estrone sulfate (ES) uptake in stably transfected human embryonic kidney-293 cells. Melphalan had no significant inhibitory effect on any OAT, whereas chlorambucil reduced OAT1-, OAT3-, and OAT4-mediated uptake of PAH or ES down to 14.6%, 16.3%, and 66.0% of control, respectively. Bendamustine inhibited only OAT3-mediated ES uptake, which was reduced down to 14.3% of control cells, suggesting that it interacts exclusively with OAT3. The IC50 value for OAT3 was calculated to be 0.8 μM. Real-time PCR experiments demonstrated a high expression of OAT3 in lymphoma cell lines as well as primary CLL cells. OAT3-mediated accumulation of bendamustine was associated with reduced cell proliferation and an increased rate of apoptosis. We conclude that the high efficacy of bendamustine in treating CLL might be partly contributed to the expression of OAT3 in lymphoma cells and the high affinity of bendamustine for this transporter.
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany; and yohannes.hagos@med.uni-goettingen.de.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany; and.
authors.forename: Philip
authors.initials: P
authors.lastname: Hundertmark
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany; and.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Shnitsar
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany; and.
authors.forename: Venkata V V R
authors.initials: VV
authors.lastname: Marada
authors.affiliation: Klinik für Hämatologie und Onkologie, Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Göttingen, Germany; and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008558:Melphalan / Q000378:metabolism / Q000494:pharmacology; D009588:Nitrogen Mustard Compounds / Q000378:metabolism / Q000494:pharmacology*; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D002699:Chlorambucil; D004970:Estrone; D000069461:Bendamustine Hydrochloride; D008558:Melphalan; C017296:estrone sulfate; D010130:p-Aminohippuric Acid
keywords: bendamustine; chlorambucil; chronic lymphocytic leukemia; cytostatics; organic anion transporter; solute carrier family 22; uptake transporter