T63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through activation of the reactive oxygen species-FOXO3a pathway in lung cancer cells
T63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through activation of the reactive oxygen species-FOXO3a pathway in lung cancer cells
复制标题
T63 是一种新型 4-亚芳基姜黄素类似物，通过激活肺癌细胞中的活性氧 - FOXO3a 途径诱导细胞周期停滞和细胞凋亡。
DOI：
10.1016/j.freeradbiomed.2012.10.537
复制
发表时间：
2012-12-15
影响因子：
7.4
通讯作者：
Bu, Xian-Zhang
中科院分区：
文献类型：
--
作者：
Liu, Hao;Zhou, Bin-Hua;Bu, Xian-Zhang
姜黄素（Curcumin，Diferuloylmethane）是姜黄（Curcumalonga）中的一种天然多酚类化合物，具有多种抗肿瘤活性。163是一种新的4-芳亚基姜黄素类似物，具有抑制肺癌细胞增殖的作用。然而，其确切的分子抗肿瘤机制尚未得到很好的阐明。T63能显著抑制人肺腺癌细胞株A549和H460的增殖，并诱导细胞周期阻滞于G0/G1期，诱导细胞凋亡。我们发现活性氧（ROS）激活的FOXO 3a级联在T63诱导的细胞增殖抑制中起着核心作用。从机制上讲，T63通过激活p38 MAPK和抑制ART诱导FOXO 3a表达和核转位，随后升高FOXO 3a靶基因的表达，包括p21，p27和Bim，然后增加活化的caspase-3水平，降低细胞周期蛋白D1水平。此外，抗氧化剂N-乙酰半胱氨酸显著阻断了上述作用，小干扰RNA介导的FOXO 3a敲低也显著降低了T63诱导的细胞周期阻滞和凋亡。体内实验表明，T63显著抑制A549肺癌异种移植瘤的生长，与肿瘤组织中的增殖抑制和凋亡诱导相关，而不诱导任何显著的主要器官相关毒性。这些数据表明，新的姜黄素类似物T63是一种有效的抗肿瘤剂，诱导细胞周期阻滞和凋亡，并具有显着的治疗肺癌的潜力。(C)2012 Elsevier Inc. All rights reserved.
Curcumin (diferuloylmethane) is a natural polyphenol product of the plant Curcuma longa and has a diversity of antitumor activities. 163, a new 4-arylidene curcumin analogue, was reported to inhibit proliferation of lung cancer cells. However, its precise molecular antitumor mechanisms have not been well elucidated. Here, we showed that T63 could significantly inhibit the proliferation of A549 and H460 human lung cell lines via induction of G0/G1 cell cycle arrest and apoptosis. We found that the reactive oxygen species (ROS)-activated FOXO3a cascade plays a central role in T63-induced cell proliferation inhibition. Mechanistically, enhancement of ROS production by T63 induced FOXO3a expression and nuclear translocation through activation of p38MAPK and inhibition of ART, subsequently elevating the expression of FOXO3a target genes, including p21, p27, and Bim, and then increased the levels of activated caspase-3 and decreased the levels of cyclin D1. Moreover, the antioxidant N-acetylcysteine markedly blocked the above effects, and small interfering RNA-mediated knockdown of FOXO3a also significantly decreased T63-induced cell cycle arrest and apoptosis. In vivo experiments showed that T63 significantly suppressed the growth of A549 lung cancer xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. These data indicated that the novel curcumin analogue T63 is a potent antitumor agent that induces cell cycle arrest and apoptosis and has significant therapeutic potential for lung cancer. (C) 2012 Elsevier Inc. All rights reserved.