Expression of organic anion-transporting polypeptides 1B1 and 1B3 in ovarian cancer cells: relevance for paclitaxel transport.

摘要

PURPOSE: Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy. Organic anion-transporting polypeptides (OATPs) mediate the uptake of clinically important drugs thereby effecting intracellular drug accumulation. In this study, we investigated whether OATPs may also contribute to paclitaxel transport in estrogen-responsive and estrogen-independent ovarian carcinoma cell lines and tumor tissue. METHODS: Expression of all 11 human OATPs in human ovarian cancer tissue samples and in the ovarian carcinoma cell lines OVCAR-3 and SK-OV-3 was investigated using real-time RT-PCR. Kinetic analysis of paclitaxel uptake was characterized in both cell lines and in OATP-transfected Xenopus laevis oocytes. Cytotoxicity of paclitaxel in OVCAR-3, SK-OV-3 and OATP1B1- and OATP1B3-transfected SK-OV-3 cells was performed using the CellTiter-Glo assay. RESULTS: OATP1B1 and OATP1B3 are active paclitaxel transporters in transfected X. laevis oocytes. Real-time RT-PCR analysis revealed expression of both OATPs in human ovarian cancer tissue specimens and in cancer cell lines. The higher mRNA levels for OATP1B1 and OATP1B3 found in SK-OV-3 cells correlated with higher initial uptake rates for paclitaxel. In addition, cytotoxicity studies with OATP1B1- and OATP1B3-transfected SK-OV-3 cells demonstrated lower IC(50) values compared to cells transfected with the empty vector. CONCLUSIONS: Our results revealed OATP1B1 and OATP1B3 as high-affinity paclitaxel transporters expressed in ovarian cancer cell lines and tumor tissues, suggesting a role for these polypeptides in the disposition of paclitaxel during therapy.