The Differential Effects and Mechanism of Zoledronic Acid-induced Cytotoxicity on Human Breast Cancer Cells under Normoxic and Hypoxic Conditions

• Main Authors: Chia-Ling Chang, 張佳鈴
• Other Authors: Chin-Wen Chi
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/95527481856730181899

碩士 === 國立陽明大學 === 藥理學研究所 === 98 === Zoledronic acid (ZOL) is used for treating bone metastasis, hypercalcemia of malignancy, multiple myeloma, and the related diseases of bone. At present, many studies have reported direct anti-breast cancer effects of ZOL. Combined administration of anticancer agents with ZOL may improve treatment of osteosarcoma, lung cancer, prostate cancer, and breast cancer. Previously, it was found that the in vivo effective dose of ZOL on cancer cells was lower than that of in vitro experiments. Additionally, anticancer effects of the same drug were different under normoxic and hypoxic conditions. The objective of this study was to compare and examine the anticancer effects and mechanism of ZOL on human breast cancer cells between normoxic and hypoxic conditions. MCF-7, MCF-7/ADR, and MDA-MB-231 cells were treated with 0.1 to 100 μM of ZOL for 24 to 72 hours. Under normoxic condition, ZOL-treatment of MCF-7 cells resulted in a dose- and time-dependent cytostatic effect using MTT and trypan blue exclusion assays. In contrast, ZOL treatment resulted in cytotoxic effect of MCF-7 cells under hypoxic condition. On the other hand, ZOL-treatment of MCF-7/ADR and MDA-MB-231 cells resulted in cytotoxic effect under both normoxic and hypoxic conditions. Flow cytometry analyses of cell cycle in ZOL-treated cells showed that percentages of different phases of cells were increased under normoxic and hypoxic conditions. Moreover, a sub-G0/G1 peak was higher under hypoxic condition than normoxic condition. Western blot analysis revealed the mechanism of ZOL-induced growth inhibition, involved in Akt/mTOR, MAPK and apoptosis pathways. ZOL treatment decreased the level of p-Akt, p-mTOR, p-ERK1/2, survivin, and Bcl-2/Bcl-xL protein and increased the level of caspase 3. Furthermore, ZOL-inhibited the expression of HIF-1α under hypoxic condition. These results suggested that the effect of ZOL-induced cytotoxicity under hypoxic condition better than under normoxic condition.