博士 / 東海大學 / 生命科學系 / 106 / Ovatodiolide, a kind of macrocyclic diterpenoid, is a bioactive ingredient isolated from the traditional Chinese medicinal herb Anisomeles indica, which possesses anti-bacterial and anti-inflammatory properties. However, the anti-cancer activity and its molecular mechanisms of Ovatodiolide have been limitedly reported. Here, we showed that ovatodiolide inhibited the growth and retarded the cell cycle progression at the G2/M phase in human lung cancer A549 and H1299 cells. The ovatodiolide-mediated G2/M phase arrest was associated with the decrease of Cyclin B1 and CDC25C levels, as well as the increase of p21WAF1/CIP1 expression. Besides, ovatodiolide-induced apoptosis was confirmed by enhancing annexin V binding and increasing TUNEL positive cells. Moreover, ovatodiolide-triggered apoptosis was through both intrinsic and extrinsic pathways characterized by the elevating PUMA, Bax, and DR5 proteins, decreasing Bcl-2 and Mcl-1 and activating caspase-8, caspase-9, and caspase-3. Caspase inhibitors could effectively attenuate ovatodiolide-triggered apoptosis. Furthermore, ovatodiolide stimulated intracellular reactive oxygen species (ROS) production and induced DNA damage response signaling pathway, including ATM/ATR, CHK1, and CHK2 phosphorylated activation. Caffeine, an ATM/ATR inhibitor, partly rescued ovatodiolide-mediated cell cycle arrest and apoptosis, but not ROS generation. Nevertheless, antioxidant N-acetyl-cysteine almost completely blocked ovatodiolide- mediated molecular events, including ATM, ATR, CHK1, CHK2 and CDC25C activation, and p21WAF1/CIP1, Bax and DR5 expression, as well as G2/M arrest and apoptosis. These observations suggest that ovatodiolide stimulates intracellular ROS generation, causes oxidative stress and DNA damage; subsequently, provokes DNA damage signaling pathways, eventually leads to block cell cycle at the G2/M phase and trigger apoptosis in human lung cancer A549 and H1299 cells.
| Identifer | oai:union.ndltd.org:TW/106THU00112010 |
| Date | January 2018 |
| Creators | YU, CHEN-YUAN, 余振源 |
| Contributors | HWANG, GUANG-YUH, HSU, SHIH-LAN, 黃光裕, 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 | 106 |
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