Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2) |
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Authors: | H Burger A Zoumaro-Djayoon AWM Boersma J Helleman EMJJ Berns RHJ Mathijssen WJ Loos EAC Wiemer |
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Affiliation: | Department of Medical Oncology, Erasmus Medical Center Rotterdam – Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Rotterdam, The Netherlands |
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Abstract: | Background:Solute carriers (SLCs), in particular organic cation transporters (OCTs), have been implicated in the cellular uptake of platinum-containing anticancer compounds. The activity of these carriers may determine the pharmacokinetics and the severity of side effects, including neuro- and nephrotoxicity of platinum-based chemotherapy. As decreased drug accumulation is a key mechanism of platinum resistance, SLCs may also contribute to the development of resistance. Here, we define the role of hSLC22A2 (OCT2) in the cellular uptake of platinum compounds.Experimental approach:Human embryonic kidney (HEK) 293 cells stably expressing the hSLC22A2 gene (HEK293/hSLC22A2) were used in platinum accumulation studies. Following a 2 h exposure to various platinum compounds (100 µM), intracellular platinum levels were determined by flameless atomic absorption spectrometry.Key results:HEK293/hSLC22A2 cells, compared with HEK293/Neo control cells, displayed significant increases in oxaliplatin (28.6-fold), PtDACH]Cl2 (20.6-fold), ormaplatin (8.1-fold), tetraplatin (4.5-fold), transplatin (3.7-fold) and cisplatin (1.3-fold), but not carboplatin. SLC22A2-mediated transport could be inhibited by 1-methyl-4-phenylpyridinium. Furthermore, hSLC22A2-mediated oxaliplatin and cisplatin accumulation was time- and concentration-dependent, but non-saturable. Expression of hSLC22A2 in HEK293 cells resulted in enhanced sensitivity to oxaliplatin (12-fold) and cisplatin (1.8-fold). Although, hSLC22A2 mRNA expression was frequently found in ovarian cancer cell lines, its expression in clinical ovarian cancer specimens (n= 80) was low and did not correlate with the treatment outcome of platinum-based regimens.Conclusions and implications:The hSLC22A2 drug transporter is a critical determinant in the uptake and cytotoxicity of various platinum compounds, particularly oxaliplatin. |
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Keywords: | platinum uptake cisplatin oxaliplatin drug resistance solute carrier (SLC) organic cation transporter (OCT) SLC22A2 |
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