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ABSTRACT
Introduction and Objective
Cholangiocarcinoma (CCA) is one of the major health concerns of the population in the northeast Thailand. Since most patients are not candidates for complete tumor resection, chemotherapy is an alternative left. However, drug resistance is a major cause of failure of cancer chemotherapy. Nrf2 is a key transcription factor regulated antioxidant enzymes which are contributed to cytoprotection in normal cells as well as tumor cells. We determined whether CCA cells activated the Nrf2 signaling system as an adaptive protection response to anticancer drugs.
Methods
KKU100 cells were treated with anticancer drugs, including 5-fluorouracil, doxorubicin, gemcitabine, cisplatin and tetrahydrocurcumin. The cell viability was determined by acridine orange/ethidium bromide (AO/EB) staining method. After drug treatment, culture cells were prepared for nuclear and cytosol fractions. Nrf2 and some antioxidant proteins were evaluated by Western immunoblotting in nuclear and cytosol protein, respectively.
Results
KKU-100 cells were sensitivity to anticancer drugs as follows doxorubicin, gemcitabine, cisplatin, tetrahydrocurcumin and 5-fluorouracil, respectively. Gemcitabine and other drugs, except 5-fluorouracil remarkably induced apoptotic cell death. Additionaly, by Western analysis, it was found that Nrf2 was constitutively expressed at basal state and was activated at early time of 6 hours by tetrahydrocurcumin, cisplatin, and gemcitabine. Nrf2 activation by those treatments was declined at 18 h where gemcitabine and doxrubicin became increase in expression. In evaluation of the downstream genes, NQO1 was up-regulated by treatments with tetrahydrocurcumin and cisplatin, whereas HO-1 was increased expression by gemcitabine as early as 6 hours.
Conclusion
CCA cells responded to anticancer drugs by activation of Nrf2 and down-stream genes probably exerting cytoprotection and resistance to the drugs. CCA cells may employ a distinct mechanism in resistance to 5-fluorouracil.
This work was supported by Thailand Research Fund (TRF), the Office of the Higher Education Commission through SHeP-GMS of Khon Kaen University, and the Royal Golden Jubilee Ph.D. Program (for PS).
Keywords : Nrf2, cholangiocarcinoma, chemotherapy, cytoprotection
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