title: Involvement of ROS-p38-H2AX axis in novel curcumin analogues-induced apoptosis in breast cancer cells.
abstract: Curcumin-based structural modification for developing more effective curcumin analogues has been drawning increasing attention. As alternative approach, using LC/MS guided purification, we previously obtained a series of novel natural terpene-conjugated curcuminoids from turmeric, and some of them exhibited even more potent anti-cancer activity against multiple types of cancer cells than curcumin. The purpose of this follow-up study was designed to decipher the mechanisms involved in anti-cancer activity of these novel curcumin analogues. Apoptosis was evaluated using sub-G1 analysis by flow cytometry and Cell Death ELISA Kit. Changes of protein expression were analyzed by western blotting. RNA interference was employed to inhibit expression of specific protein. We found that bisabolocurcumin ether (T1) and demethoxybisabolocurcumin ether (T2) were able to trigger much stronger apoptosis induction in multiple types of cancer cells than curcumin, which was attributed to persistent and stronger ROS generation. ROS induction by T1 resulted in activation of p38/H2AX axis and p53. Inhibition of p38/H2AX led to a significant reduction of apoptosis, whereas inactivation of p53 caused a dramatically enhanced H2AX phosphorylation and apoptosis induction, suggesting activation of p38/H2AX contributed to apoptosis induction by T1, whereas p53 activation protected novel curcumins-induced apoptosis via suppression of H2AX activation. Our findings provide mechanistic support for the potential use of terpene-conjugated curcuminoids as a novel class of cancer chemopreventive agents. © 2015 Wiley Periodicals, Inc.
authors: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors: Yinhui
authors: Y
authors: Dong
authors: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors: Shutao
authors: S
authors: Yin
authors: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors: Xinhua
authors: X
authors: Song
authors: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors: Yazhen
authors: Y
authors: Huo
authors: College of Veterinary Medicine, China Agricultural University, Beijing Key Laboratory of Functional Food From Plant Resources, Haidian District, Beijing, China.
authors: Lihong
authors: L
authors: Fan
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors: Min
authors: M
authors: Ye
authors: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Haidian District, Beijing, China.
authors: Hongbo
authors: H
authors: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D013729:Terpenes; D048051:p38 Mitogen-Activated Protein Kinases; D003474:Curcumin
keywords: H2AX; apoptosis; curcumin; p38; p53; terpene-conjugated curcuminoids