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

• Published in: Biomedicine & pharmacotherapy Vol. 65; no. 6; pp. 417 - 426
• Main Authors: Svoboda, Martin, Wlcek, Katrin, Taferner, Barbara, Hering, Steffen, Stieger, Bruno, Tong, Dan, Zeillinger, Robert, Thalhammer, Theresia, Jäger, Walter
• Format: Journal Article
• Language: English
• Published: France Elsevier SAS 01.09.2011
• Subjects: Adult; Animals; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Biological Transport; Cell Line, Tumor; Cell Survival - drug effects; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Internal Medicine; Kinetics; Medical Education; Middle Aged; Neoplasm Grading; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; OATPs; Oocytes - metabolism; Organic Anion Transport Protein 1 - genetics; Organic Anion Transport Protein 1 - metabolism; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Independent - genetics; Organic Anion Transporters, Sodium-Independent - metabolism; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; OVCAR-3; Paclitaxel; Paclitaxel - metabolism; Paclitaxel - pharmacology; PCR; Recombinant Proteins - metabolism; RNA, Messenger - metabolism; SK-OV-3; Solute Carrier Organic Anion Transporter Family Member 1b1; Solute Carrier Organic Anion Transporter Family Member 1B3; Xenopus laevis; OVCAR-3; SK-OV-3; OATPs; PCR; Paclitaxel; Ovarian cancer
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2011.04.031

Abstract 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 IC50 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.