Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2).

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Burger H, Zoumaro-Djayoon A, Boersma AW, Helleman J, Berns EM, Mathijssen RH, Loos WJ, Wiemer EA

Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2).

Br J Pharmacol. 2010 Feb;159(4):898-908. doi: 10.1111/j.1476-5381.2009.00569.x. Epub 2010 Jan 8.

PubMed ID

20067471 [ View in PubMed

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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 microM), 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), Pt[DACH]Cl(2) (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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cisplatin	Solute carrier family 22 member 2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Oxaliplatin	Solute carrier family 22 member 2	Protein	Humans	No	Substrate	Details