Abstract
Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.
Highlights
Colon cancer is one of the most commonly occurring tumors and a major cause of cancer-related deaths worldwide, which accentuates the need for effective strategies to prevent and treat this malignancy
Consistent with previous findings, we found that epidermal growth factor receptor (EGFR) inhibitor gefitinib alone modestly decreased the cell viability in SW1116 and PC-9 colon cancer cell lines carrying wild-type EGFR gene [27,28]
DNA demethylating agents induced apoptosis are minimal on its own, they exert potential to enhance the effects of other chemotherapeutics, such as DNA damaging agent cisplatin [35]
Summary
Colon cancer is one of the most commonly occurring tumors and a major cause of cancer-related deaths worldwide, which accentuates the need for effective strategies to prevent and treat this malignancy. Therapies available for treatment of colon cancer include surgery, radiation therapy, chemotherapy, immunomodulatory therapy, and molecularly targeted therapies such as antivascular endothelial growth factor receptor (VEGFR) and antiepidermal growth factor receptor (EGFR) therapy [1,2]. Among these molecularly targeted treatments, EGFR-targeted therapy as one of the important clinical strategies has been increasingly widely applied in patients with metastatic colon cancer [3]. As activation of EGFR is correlated with colon cancer progression, the EGFR has been the target of anticancer drug development efforts These strategies targeting EGFR include using monoclonal antibodies such as cetuximab, and small molecular tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Efforts are ongoing for the development of anti-colon cancer regimens that would combine gefitinib with other drugs
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