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Interaction of human organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP)
Venkata V V R Marada1, Saskia Flörl2, Annett Kühne2
1Institut für Vegetative Physiologie und Pathophysiologie, Universitätmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
Abstract:
The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33μM, 26.4±2.34μM and 10.4±0.45μM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan.
Insights
The organic anion transporter 2 (OAT2) mediates the uptake of chemotherapy drugs like bendamustine and irinotecan into cancer cells. This transporter
Area of Science:
- Pharmacology and Toxicology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy resistance is a major challenge in cancer treatment, often linked to drug transport proteins.
- While efflux transporters are well-studied, the role of uptake transporters in antineoplastic drug action remains less understood.
- Organic anion transporter 2 (OAT2) and sodium taurocholate cotransporting polypeptide (NTCP) are liver-expressed uptake transporters with potential roles in drug disposition.
Purpose of the Study:
- To investigate the interaction of OAT2 and NTCP with commonly used antineoplastic agents.
- To determine if OAT2 and NTCP influence the cellular uptake and efficacy of chemotherapy drugs.
- To characterize the kinetic parameters of OAT2 for identified drug substrates.
Main Methods:
- Stable transfection of human embryonic kidney cells with OAT2 and NTCP.
- Assay of OAT2-mediated [(3)H] cGMP uptake inhibition by antineoplastic drugs.
- Determination of inhibition constants (Ki) for OAT2-drug interactions.
- Measurement of caspase-3 activity to assess drug-induced apoptosis.
- High-performance liquid chromatography (HPLC) analysis of intracellular drug accumulation.
Main Results:
- NTCP showed no significant interaction with the tested cytostatics.
- OAT2 function was strongly inhibited by bendamustine, irinotecan, and paclitaxel, with determined Ki values.
- Bendamustine uptake by OAT2 increased caspase-3 activity, suggesting OAT2 mediates its transport.
- Irinotecan accumulation was higher in OAT2-expressing cells and diminished by OAT2's substrate, cGMP, confirming OAT2-mediated uptake.
Conclusions:
- OAT2 plays a significant role in the uptake of several key antineoplastic drugs, including bendamustine and irinotecan.
- The interaction of OAT2 with these drugs suggests its potential involvement in chemotherapy efficacy and resistance.
- Further research into OAT2's role in cancer drug transport is warranted for therapeutic development.
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