| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 98 === Bone metastases are common phenomena during breast cancer progression. Under normal condition, bone remodeling is regulated by the balance between bone resorption via osteoclasts and bone formation by osteoblasts. When cancer cells migrate to bone tissue, the activity and proliferation of osteoclasts are up-regulated and thus result in an increase in bone resorption. Clinically, bisphosphonates (BPs) are usually used to treat patients with increased bone resorption. Several lines of evidence reveled that BPs could inhibit the mevalonate pathway of cholesterol synthesis and/or block the activity of the mitochondrial adenine nucleotide translocase (ANT), which lead to a decrease in bone resorption and an increase in apoptosis of osteoclasts. Recent evidence revealed that BPs also have direct anti-tumor effects. In this study, we investigated the potential mechanism for nitrogen-containing bisphosphonates (zoledronic acid) induced cell death in human breast cancer cell lines. Our results showed that zoledronic acid inhibited cell proliferation and induced cell death in dose- and time-dependent manners. The cytotoxic effects of zoledronic acid for highly metastatic and malignant breast cancer MDA-MB-231 cells as well as adriamycin-resistant MCF-7/ADR cells are more extensive than those for the adriamycin-sensitive MCF-7 cells. Treatment of zoledronic acid also reduced intracellular ATP content, oxygen consumption rate and mitochondrial membrane potential. In addition, zoledronic acid not only induces apoptosis but also activate autophagy. The levels of zoledronic acid-induced autophagy and apoptosis in MDA-MB-231 and MCF-7/ADR cells are higher than that in MCF-7 cells. Using an autophagy inhibitor 3-methyladenine and ATG7 siRNA we found that inhibition of zoledronic acid-induced autophagy increase the level of apoptosis. Therefore, these results suggest that zoledronic acid-induced autophagy has cytoprotective effect. Inactivation of autophagy might be as a new strategy to enhance zoledronic acid’s anti-cancer effect and treat zoledronic acid-resistant breasr cancer cells
|
|---|
