2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660862Gastric cancer remains a common disease with a dreary prognosis. Traditional chemotherapy and radiotherapy may be applied, but do not cure the disease. Thus, improvement of gastric cancer therapy will depend on novel therapeutic approaches. The Bcl-2 family is important in modulating sensitivity to anticancer drugs in many cancers. The BH3 mimetic ABT737 is a potent small molecule inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-xL/Bcl-w. An orally available ABT737 analogue, ABT263, is under phase I clinical trail for small cell lung cancer and leukemia. However, ABT737 resistant cells increase levels of Mcl-1 proteins, which are not targeted by ABT737. In our previous study, we determined that imiquimod, a clinical used toll-like receptor 7 agonist, can rapidly down-regulate Mcl-1 protein levels by inhibiting translation, and simultaneously induce autophagic cell death and apoptosis in basal cell carcinoma cells. We hypothesize that down-regulates Mcl-1 protein expression by imiquimod may compensate the acquired ABT737 resistance which caused by Mcl-1 up-regulation in cancer cells with ABT737 treatment alone. Thus, the combination of sub-apoptotic concentration of imiquimod with ABT737 combination may result in synergistic induction of cell death in human cancer cells including gastric cancer. However, the anti-tumor effects of imiquimod and ABT737 in gastric cancer have never been addressed before. In this study, we will examine the biological effects of imiquimod and ABT737 on gastric cancer cell lines, determine whether ABT737 is synergistically effective in killing gastric cancer cells in combination with the imiquimod in vitro and in vivo, and further evaluated their molecular mechanisms of action. This study will provide promising therapeutic potential of targeting anti-apoptotic Bcl-2 family members in treating gastric cancers, and it will validate rational molecular approaches that target anti-apoptotic defenses when developing cancer treatments.