碩士 / 國立中興大學 / 生命科學系所 / 103 / The statistic documents from Ministry of Health and Welfare indicate that lung cancer is the first leading cause of cancer mortality in Taiwan, and increased gradually nowadays. Smoking, air pollution and soot are the high risk factors of lung cancer. Surgery, chemotherapy, radiation therapy and targeted therapy are the common treatments for lung cancer patients. However, the curing rate of these patients is still limited, to develop the safe and effective therapeutic strategy or agent is urgently needed. Previous studies have shown that inhibition of cell growth and induction of cell death of lung cancer cells are the major mechanisms for cancer therapies. Anisomeles indica (A. indica), a popular Taiwanese medicinal herb, has been known with relieve heat, analgesia, detoxification and antibacterial activities, and used as a folk medicine for the treatment of rheumatoid arthritis, enteritis, and inflammation-related disorders. Ovatodiolide, a diterpenoid, is isolated form A. indica. Previous reports demonstrate that ovatodiolide inhibits the proliferation and metastasis, as well as induces apoptotic cell death in several types of human cancer cells; however, the cellular and molecular mechanisms of these ovatodiolide-mediated biological events are largely unclear. In this study, the effect and the mechanisms of ovatodiolide on human lung cancer A549 and H1299 cells were examined. Our results showed that low doses of ovatodiolide treatment inhibited the growth of lung cancer cells; however, ovatodiolide-triggered cytotoxicity occurred at high concentrations. Ovatodiolide also increased the reactive oxygen species (ROS) generation in H1299 and A549 cells. Moreover, ovatodiolide-mediated cytotoxic effect was through both extrinsic and intrnisic apoptotic pathways in A549 cells, evidenced by decrease of Bcl-2 and increase of PUMA、DR5 and Bax protein levels, as well as activation of caspases cascade. Besides, activation of JNK, p53 and C-jun signaling pathways were also observed in ovatodiolide-treated cells. Moreover, Ovatodiolide induced DNA damage and activated ATM/Chk1/Chk2 signaling axis. The Chk1and Chk2 inhibited CDC25C and CDK1 activity, consequently led to cell cycle G2/M phase arrest. Ovatodiolide-mediated ATM activation also stimulated p53 activation and downstream cell cycle-related and death-related proteins, subsequently triggered cell cycle arrest and apoptosis. Furthermore, administration of N-acetylcystein effectively reduced the activity of JNK and ATM and reversed the expression of anti-apoptotic and proapoptotic proteins, inactivated caspase cascade, as well as attenuated apoptosis induced by ovatodiolate. Overall, these findings provide evidence that ovatodiolide induced ROS generation and triggered JNK and ATM signaling pathways, activated c-Jun and p53 transcriptinal activity, and then regulated the expression of Bcl-2 family and death receptor family molecules, which activated caspase cascade, finally leading to cell cycle G2/M arrest and apoptosis in tested lung cancer A549 and H1299 cells.
| Identifer | oai:union.ndltd.org:TW/103NCHU5105048 |
| Date | January 2015 |
| Creators | Pei-Shan Hung, 洪珮珊 |
| Contributors | Shih-Lan Hsu, 徐士蘭 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 62 |
Page generated in 0.0092 seconds