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Since option of chemotherapy treatment for cholangiocarcinoma is limited, conventional chemotherapy to date have been proved to be ineffective in improving long-term survival. Currently, complete resection of the tumor is the only best choice for long-term survival. Unfortunately, the vast majority of patients with cholangiocarcinoma do not have optimal situation for curative surgery when diagnosis is confirmed. However, single-agent chemotherapy has met with only very limited success. To date, only few published series have been able to show response rate for single agent chemotherapy and very few claims have been made for prolonging survival. In addition, chemotherapy also induces acquired resistance that has been one of the most important clinical problems. At such a circumstance, there is now a real and urgent need to focus on developing novel therapeutic strategies for cholangiocarcinoma that would impact in a significant way on clinical outcome.
Accumulating evidence suggests that NQO1 is a promising therapeutic target for various tumors and NQO1 is the attractive targets in development of chemotherapy, once NQO1 plays a protective role in normal cells as well as cancer cells. Nevertheless, there is currently no specific anti-cancer drugs used in clinical and thus its therapeutic value remains unexplored. Our study demonstrated that NQO1 is a potent cytoprotective against anti cancer drugs. This possibility was illustrated by the observation that NQO1 knockdown induced apoptosis and sensitized cells to anticancer drugs. The sensitization of CCA cells by NQO1 siRNA initiates apoptotic cell death processes mediated p53 pathway.
Modulation of NQO1 may confer increased chemosensitivity of some cancers relying on NQO1. The studies on NQO1 inhibition strongly support the role of NQO1 on chemo-resistance in various cancers. Inhibition of NQO1 activity by dicoumarol has been shown to suppress urogenital and pancreatic cancer cell growth and potentiate cytotoxicity of cisplatin and doxorubicin (Matsui et al., 2010; Watanabe et al., 2006). The inhibition of NQO1 with dicoumarol was suggested to stimulate formation of superoxide, oxidative stress and subsequent suppression of pancreatic cancer cell growth and induction of apoptosis (Cullen et al., 2003; Lewis et al., 2004). However, dicoumarol has been shown to induce formation of reactive oxygen species (ROS) independently from NQO1 activity by inhibition of the mitochondrial electron transport chain (Du et al., 2006). Moreover, NQO1 may play roles in the sensitivity of CCA cells to gemcitabine. When using dicoumarol at relevant concentrations to inhibit NQO1 activity, dicoumarol enhances gemcitabine cytotoxicity in high NQO1 activity CCA cells. (Buranrat et al., 2010). In our previous study showed that CCA tissues have higher NQO1 activity and immunohistochemical localization in comparison with the apparently CCA normal tissues and cadaveric donors (ref). Moreover, in the present study, treatment with anticancer agent also strongly up-regulated NQO1 expression, imply that adaptive defense response in CCA cells is induced to tolerate the drugs. These results suggest that role of NQO1 in cytoprotection is very critical. It should be illustrious that cytoprotective effect conferred by NQO1 is response to all of anticancer drug; 5-FU, Doxo, and Gem as well and may be in some type of anticancer drugs, in spite of the different mechanisms of action of those anticancer agents. Taken together that the resistance of CCA cells to anticancer drugs is, at lest in part, due to induction of NQO1. We provide evidence that suppression of NQO1 was important in inducing CCA cells to be highly susceptible to anticancer drug effect.
Subsequently in this study, we investigated further as to how NQO1 inhibition induces the sensitization in CCA cells to anticancer agents. Since, the p53 tumor suppressor is a pivotal regulating component that senses various intrinsic and extrinsic stresses and initiates apoptotic call death (ref). In addition, it is important to determine the role of p53 pathway on the apoptotic cell death induced by NQO1 inhibition. All evidence collected from the present study indicated that NQO1 knockdown enhance anticancer drugs mediated apoptotic cell death is p53 dependent. Our study showed that NQO1 knockdown cells were treated with anticancer agents that increased levels of p53 protein. Moreover, cell inhibition observed in NQO1 knockdown cells may be partially related to growth inhibition as indicated by the observed up-regulation of p21 and Bax protein levels to cellular sensitization to apoptosis, as well as to the observed decreased levels of Cyclin D1. In our previous studies, we have also found that the combination between gemcitabine with dicoumarol (NQO1 inhibitor) modulate p53 expression, together with decreased Bcl-XL protein expression, was associated with enhanced cytotoxicity of gemcitabine (ref). In support to our suggestion of an intracellular cytoprotective NQO1 function in normal cells, as well as tumor cells, particularly when it is highly expressed (ref). Based on this fact, we found that Overexpression of NQO1 in M214 cell resulted in the decreased chemosensitivity to anticancer drugs treatment by the combination might also disrupt p53 apoptotic pathway. These results provide evidence that NQO1 overexpression is associated with poor tumor response to anticancer drugs treatment and overcome the resistance to chemotherapy of CCA.
We provide evidence that double silence of NQO1 and p53 wild type decrease the effective dose of anticancer drugs that is required for growth inhibition of CCA cells. Our finding suggest that the use of p53 siRNA may decrease the effective dose of anticancer drugs, especially DNA damaging drugs, required for treatment, thus reducing toxicity, to chemotherapeutic or chemo-preventive regimens that employ anticancer drugs; 5-FU, Doxo, and Gem should be considered for CCA. Of the factors regulating anticancer drugs induced cell apoptosis, p53 is believed to be of principal importance. Since p53 mutations are the most common genetics changes found in CCA and mutations in this gene often result in loss of this function and inactivation, defects in p53-dependent functions like apoptosis may play a significant role in resistance to chemotherapy. So, in our current study, we have for the first time provided evidence that NQO1 could act through the activation of p53 in KKU-100 CCA cell lines, with subsequent activation of the apoptotic pathway. This might lead to the increase in chemosensitivity to anticancer drugs; 5-FU, Doxo, and Gem in CCA cell line.
In conclusion, NQO showed the promising effect in cytoprotective role contributed to chemoresistance. Role of NQO1 in adaptive survival response has been investigated in CCA cells. Constitutive and inducible NQO1 expression may be contributory to chemoresistance to anticancer drugs, whereas knockdown of NQO1 sensitized CCA cells to be highly susceptible to anticancer drugs. Furthermore, the mechanism of NQO1 inhibition-induced cell killing may be mediated p53 related to suppression of apoptotic response to the chemotherapy. This study may provide evidence that suppression of NQO1 was important in inducing CCA cells to be highly susceptible to anticancer drug effect and also afford a new combination of drugs for CCA chemotherapy and further clinical studies are required and necessary.