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Abstract
BackgroundCholangiocarcinoma (CCA) is highly resistant to most of the known chemotherapeutic treatments. NAD(P)H-quinone oxidoreductase 1 (NQO1) is an antioxidant/detoxifying enzyme recently recognized as an important contributor to chemoresistance in some human cancers. However, the contribution of NQO1 to chemotherapy resistance in CCA is unknown.MethodsTwo CCA cell lines, KKU-100 and KKU-M214, with high and low NQO1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents; 5-fluorouracil (5-FU), doxorubicin (Doxo), and gemcitabine (Gem). NQO1 and/or p53 expression in KKU-100 cells were knocked down by siRNA. NQO1 was over-expressed in KKU-M214 cells by transfection with pCMV6-XL5-NQO1 expression vector. CCA cells with modulated NQO1 and/or p53 expression were treated with chemotherapeutic agents, and the cytotoxicity was assessed by SRB assay. The mechanism of enhanced chemosensitivity was evaluated by Western blot analysis.ResultsWhen NQO1 was knocked down, KKU-100 cells became more susceptible to all chemotherapeutic agents. Conversely, with over-expression of NQO1 made KKU-M214 cells more resistant to chemotherapeutic agents. Western blot analysis suggested that enhanced chemosensitivity was probably due to the activation of p53-mediated cell death. Enhanced susceptibility to chemotherapeutic agents by NQO1 silencing was abolished by knockdown of p53.ConclusionsThese results suggest that inhibition of NQO1 could enhance the susceptibility of CCA to an array of chemotherapeutic agents.
Highlights
Cholangiocarcinoma (CCA) is highly resistant to most of the known chemotherapeutic treatments
The results showed that NAD(P)H-quinone oxidoreductase 1 (NQO1) mRNA expression was suppressed by Small interfering RNA (siRNA) more than 80% at 24 hr (Figure 2A)
The results showed that the cytotoxicity of 5-FU, Doxo, and Gem were markedly decreased for NQO1over-expressed KKU-M214 cells (Figure 4C-E), indicating the protective effect of NQO1
Summary
Cholangiocarcinoma (CCA) is highly resistant to most of the known chemotherapeutic treatments. NAD(P)H-quinone oxidoreductase 1 (NQO1) is an antioxidant/detoxifying enzyme recently recognized as an important contributor to chemoresistance in some human cancers. The contribution of NQO1 to chemotherapy resistance in CCA is unknown. Cholangiocarcinoma (CCA) is a malignant cancer arising from neoplastic transformation of cholangiocytes, the epithelial cells lining of intrahepatic and extrahepatic bile duct [1,2]. Several lines of studies have shown that the NAD(P)H-quinone oxidoreductase 1 (NQO1 or DTdiaphorase, EC 1.6.99.2) is a drug metabolizing enzyme. Chronic inflammation suppresses NQO1 expression [16] and may increase susceptibility to cell injury. Since NQO1 is an antioxidant enzyme, it may protect cancer cells by removing free radicals and making cells more resistant to anticancer agents, to oxidative stress inducers
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