| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 102 === Breast cancer is the first most common cancer and the fourth most frequent oncological cause of death in women in Taiwan. There are many types of breast cancer and triple-negative breast cancer is the most malignant type of breast cancer. Bone is one of the most common metastasis site of breast cancer. Zoledronic acid (ZOL) is a bisphosphonate to treat bone metastasis. Previous report showed that BPs, especially ZOL, could inhibit human breast cancer cells invasion. Moreover, ZOL could cause tumor cell apoptosis, inhibition of tumor cell adhesion and have anti-angiogenic effects. Previous studies have showed that treatment of ZOL on different lines of triple-negative breast cancer cells under hypoxia condition can showed stronger cytotoxic effect as compared with normoxia condition. The preliminary results showed that treatment of ZOL in breast cancer cells induces cell autophagy and apoptosis. In addition, bafilomycin A1 (BA1), which is a late-stage autophagic inhibitor and prevents the fusion of lysosome with autophagosome, can reduce ZOL-induced cell death. Because hypoxia can induce cell acidosis and BA1 can inhibit lysosomal acidification and change the pH value of tumors, I hypothesised that intracellular acidification or environmental acidosis might be involved in the ZOL-induced cell death. In this study, I used BCECF-AM, which is the most widely used intracellular pH probe, to check the pH change of the triple-negative breast cancer cells under ZOL treatment. The results revealed that the pH value becomes lower in the breast cancer cells under the ZOL treatment, and the pH value becomes higher in the breast cancer cells under the BA1 combined with ZOL. Then I changed the extracellular pH value and the expression level of the ionic channel NHE-1 that is function in the regulation of the intercellular and extracellular pH value. But there was no significant change in the ZOL-induced triple negative breast cancer cell death. These results suggested that the mechanisms by which ZOL induces breast cancer cell death is related to the intracellular pH change. But it is not proved that the mechanisms is related to the extracellular pH change. In summary, it still needs more investigations to confirm whether the ZOL-induced breast cancer cell death is mainly caused by the pH change in cancer cells .
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