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Abstract
BackgroundCholangiocarcinoma (CCA), an epithelial malignancy of the biliary tree, is one of the aggressive cancers with poor prognosis and unsatisfactory response to chemotherapy with acquired resistance. NAD(P)H-quinone oxidoreductase 1 (NQO1), an antioxidant/detoxifying enzyme, plays important roles in chemo-resistance and proliferation in several cancer cells. The study aimed to investigate the inhibitory effect of β-eudesmol on NQO1 enhanced chemotherapeutic effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) in the high NQO1-expressing human CCA cell line, NQO1-KKU-100. In addition, the molecular events associated with the inhibition of the cell proliferation, cell migration, and induction of apoptosis were investigated.MethodsHuman CCA KKU-100 cells were exposed to β-eudesmol at various concentrations. NQO1 enzyme activity and protein expression were measured by enzymatic assay and Western blot analysis, respectively. Sulforhodamine B (SRB) assay and wound healing assay were performed to detect the inhibitory effect of β-eudesmol on cell proliferation, cell migration, and sensitivity to 5-FU and DOX. Apoptotic induction was detected by flow cytometry with annexin V/PI and DAPI nuclear staining. Caspase 3/7 activation was determined by fluorescence microscopy. The mechanism of enhanced chemo-sensitivity was evaluated by Western blot analysis.Resultsβ-Eudesmol significantly suppressed NQO1 enzyme activity (both in KKU-100 cells and cell lysates) and protein expression in KKU-100 cells in a concentration-dependent manner. β-Eudesmol exhibited potent cytotoxicity on KKU-100 cells with mean ± SD IC50 values of 47.62 ± 9.54 and 37.46 ± 12.58 μM at 24 and 48 h, respectively. In addition, it also potentiated the cytotoxic activities and inhibitory activities of 5-FU and DOX on cell migration through induction of cell apoptosis and activation of caspase 3/7. Western blot analysis suggested that β-eudesmol enhanced chemosensitivity was associated with the suppression of NQO1 protein and activation of Bax/Bcl-2 protein expression ratio in CCA cells.Conclusionsβ-Eudesmol may serve as a potential anti-CCA candidate particularly when used in combination with conventional chemotherapeutics. The mechanisms involved may be mediated via NQO1 suppression-related apoptosis pathway.
Highlights
Cholangiocarcinoma (CCA), an epithelial malignancy of the biliary tree, is one of the aggressive cancers with poor prognosis and unsatisfactory response to chemotherapy with acquired resistance
We have previously reported that β-eudesmol exerts potent growth inhibitory activity on CCA cells which might be linked to its suppressive effect on heme oxygenase-1 (HO-1) production, STAT1/3 activation, and NF-κB downregulation [39]
For β-eudesmol, significant inhibitory activity on NAD(P)Hquinone oxidoreductase 1 (NQO1) activity was observed at 30 and 100 μM (37.68 and 50.06%, respectively). β-Eudesmol produced an inhibitory effect on the NQO1 activity of the cell lysates in a concentration-dependent manner (Fig. 1b)
Summary
Cholangiocarcinoma (CCA), an epithelial malignancy of the biliary tree, is one of the aggressive cancers with poor prognosis and unsatisfactory response to chemotherapy with acquired resistance. Cholangiocarcinoma (CCA) is an extremely aggressive malignant tumor of the bile duct that becomes one of the major health problems worldwide. It is originating from the epithelial cells of the extrahepatic or intrahepatic bile ducts [1]. Multiple mechanisms involved in resistance of CCA to chemotherapeutic agents have been proposed. These include alteration of drug metabolizing enzymes, efflux transporters, cytoprotective enzymes, or derangement of intracellular signaling system [7, 8]. Novel effective therapy to overcome the chemoresistance of CCA is urgently needed
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