Expression of Human Organic Cation Transporter 3 in Kidney Carcinoma Cell Lines Increases Chemosensitivity to Melphalan, Irinotecan, and Vincristine

Abstract

Renal cell carcinoma (RCC) is usually chemoresistant. This chemoresistance could be overcome if specific cytostatics are applied for which the RCC expresses an uptake transporter. In the present study, we investigated the expression of solute carrier (SLC) transporters in different RCC lines and their ability to interact with chemotherapeutics. We tested five RCC lines for the expression of different SLCs by reverse transcription-PCR and TaqMan real-time PCR. In two of five RCC lines, A498 and 7860, we observed a highly significant expression of SLC22A3 (hOCT3 ]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays on CHO-hOCT3, A498 (high expression of hOCT3), and ACHN cell lines (low expression of hOCT3). The growth of CHO-hOCT3 was inhibited by 20% more with irinotecan and by 50% more with vincristine compared with nontransfected CHO cells. Melphalan produced 20% to 30% more inhibition in hOCT3-expressing cells compared with nonexpressing control cells. Similar results were obtained for A498 and ACHN cells. Thus, our data support the hypothesis that the sensitivity of tumor cells to chemotherapeutic treatment depends on the expression of transporter proteins mediating specific drug accumulation into target cells.

Human Organic Cation Transporter 1 Is Expressed in Lymphoma Cells and Increases Susceptibility to Irinotecan and Paclitaxel

“…Cisplatin, a platinum-based antineoplastic, is specifically transported by OCT2 (Ciarimboli et al, 2005), whereas OCT6 transports the antineoplastic doxorubicin (Okabe et al, 2005). We recently demonstrated the involvement of OCT3 in the uptake of the antineoplastics irinotecan, melphalan, and vincristine as well as the OCT3-mediated cytotoxicity of these drugs in renal carcinoma cell lines (Shnitsar et al, 2009).…”

“…SLC transporters undergo sequential conformational changes during the transport cycle, and some of these proteins are capable of transporting more than one substrate simultaneously (Bergeron et al, 2008). The transport of antineoplastics by SLC transporters has been reported previously for organic cation transporter 1 (OCT1) (SLC22A1) as a transporter of imatinib, oxaliplatin, and picoplatin (White et al, 2006;Zhang et al, 2006;More et al, 2010) and OCT2 (SLC22A2) as a transporter of cisplatin and oxaliplatin (Zhang et al, 2006), whereas OCT3 (SLC22A3) mediated the uptake of irinotecan, vincristine, and melphalan (Shnitsar et al, 2009).…”

“…These include the altered activity of transcriptional factors, gene polymorphisms, and changes in the methylation status of promoters (Kim et al, 2006). In contrast to ABC transporters, uptake transporters may increase the intracellular concentrations of selected antineoplastic drugs and elevate the chemosensitivities of tumor cells (Shnitsar et al, 2009).…”

285 Downregulation of Organic Cation Transporters Oct1 (Slc22a1) and Oct3 (Slc22a3) in Human Hepatocellular Carcinoma and Their Prognostic Significance

“…In colorectal cancer OCTs are determinants of oxaliplatin cytotoxicity [11,[25][26][27]. Moreover, SLC22A3 expression in renal cell carcinoma cell lines enhances the sensitivity towards chemotherapeutics as melphalan, irinotecan and vincristin [28].…”

SLC22A3 (Solute carrier family 22 member 3)

“…Renal cell carcinomas are mainly resistant to chemotherapies, which appear to be dependent upon the expression of transporter proteins that include SLC22A3 (Shnitsar et al, 2009).…”