Sirinapa Sribenja, Nichapavee Natthasirikul, Kulthida Vaeteewoottacharn, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Patcharee Jearanaikoon, Sopit Wongkham
Introduction and aim. 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic drug in the treatment of cholangiocarcinoma (CCA). Since development of drug resistance to 5-FU in CCA patients is the primary cause of treatment failure, a better understanding of the mechanism of drug resistance of this cancer is essential to improve the efficacy of 5-FU in CCA therapy. Material and methods. A 5-FU resistant CCA cell line (M214-5FUR) for a comparative chemo-resistance study was established. Real time RT-PCR was used to determine gene expression levels. Cell cytotoxicity was measured by the MTT assay. Protein expression levels were detected by the immunofluorescene method. Results. It was found that 5-FU resistance was associated with the overexpression of TB10 in CCA cell lines. 5-FU treatment at various concentrations induced the expressions of TB10 and ABC transporters (ABCB1, ABCG2 ABCA3) in two CCA cell lines, KKU-M055 and KKU-M214. M214-5FUR, a 5-FU-resistant cell line, exhibited a 5-FU resistant phenotype with a 16-fold extremely high expression of Tb10 and ABC transporters, as compared to the parental cells, KKU-M214. siRNA targeted to TB10 significantly reduced expression of ABC transporters tested in the M214-5FUR cells (P < 0.05). Conclusions. The present novel findings of TB10 connected with drug resistance as shown in this study provides a new insight for the therapeutic value of T?10 as a predictive biomarker of 5-FU chemoresistance. Inhibiting TB10 may be a valuable adjunct for suppression of ABC transporters and sensitizing chemotherapy treatment, especially 5-FU in CCA patients.
Key words. T?10. 5-FU, Chemotherapeutic resistance, ATP-binding cassette transporters, Multidrug resistance