Subamolide A induces two distinct modes of human lung cancer cell death: senescence-like phenotype and mitotic catastrophe accompanied by apoptosis

• Main Authors: Ching-Wen Wen, 溫靖雯
• Other Authors: Ya-Lin Hsu
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/16208544687337052672

碩士 === 高雄醫學大學 === 醫學研究所 === 100 === Lung cancer is one of the most common cancer deaths in both men and women throughout the world. According to the U.S. National Cancer Institute, approximately one out of every 14 men and women in the U.S. will be diagnosed with cancer and about 28% of them will eventually die due to lung cancer in 2011. Owing to lung cancers poor prognosis and high death rate, it is urgent and of priority to develop a chemopreventive or chemotherapy drug. This study first investigates the anticancer effect of Subamolide A, isolated from Cinnamomum subavenium, on human non-small cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Subamolide A results in the antiproliferative ability of both lung cancers. Subamolide A induced lung cancer cell death was first by triggering senescence-like phenotype with enlargement of cells and increased senescence-associated β-galactosidase activity, followed by abnormal mitosis catastrophe. In addition, exposure of A549 and NCI-H460 cells to Subamolide A resulted in cellular ROS generation with the induction of ATM phosphorylation and ATF3 activation, which were inhibited by antioxidant EUK8. Besides, Subamolide A treated cells that undergo mitotic catastrophe and thus initiate senescence-like apoptosis is not only by activating Erk1/2, but also through p53-dependent pathways in both lung cancers. Furthermore, daily Subamolide A i.p. injection in nude mice after A549 transplantation resulted in a 50% decrease of mean tumor volume, compared with vehicle-treated group. Taken together, our data demonstrates that cell death of lung cancer cells in respond to Subamolide A is dependent upon ROS generation, triggering senescence-like phenotype and mitotic catastrophe as well as apoptosis pathways. Therefore, Subamolide A may be a novel anticancer agent for the treatment of non-small cell lung cancer.