SZ-685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway
SZ-685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway
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SZ-685C 是一种海洋蒽醌，是一种有效的细胞凋亡诱导剂，通过抑制 Akt/FOXO 途径具有抗癌活性
DOI：
10.1111/j.1476-5381.2009.00577.x
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发表时间：
2010-02-01
影响因子：
7.3
通讯作者：
Yuan, Jie
中科院分区：
文献类型：
--
作者：
Xie, Gui'e;Zhu, Xun;Yuan, Jie
背景与目的：本研究的目的是研究从海洋来源的红树林内生真菌中分离得到的蒽环类抗生素SZ-685 C的抗肿瘤活性，并探讨其抗肿瘤活性的分子机制。实验方法：采用MTT法研究SZ-685 C对肿瘤细胞株活力的影响。通过Annexin V-异硫氰酸荧光素/碘化丙啶染色、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和caspase活化分析来评估SZ-685 C诱导的细胞凋亡。采用蛋白质印迹分析研究了SZ-685 C对Akt/FOXO途径的影响，并在MDA-MB-435乳腺癌异种移植模型中检查了体内抗肿瘤功效。关键结果：SZ-685 C抑制了来自人乳腺癌、前列腺癌、胶质瘤和肝癌的六种癌细胞系的增殖（IC 50值范围为3.0至9.6 μ M）以及小鼠乳腺癌异种移植物的生长。SZ-685 C通过外源性和内源性凋亡途径具有直接的凋亡诱导作用，如通过激活caspase-8和9以及效应caspase-3和聚（ADP-核糖）聚合酶所示。在SZ-685 C处理的癌细胞中，Akt及其下游效应物叉头盒蛋白O 1和叉头盒蛋白O3 a的磷酸化下调。此外，促凋亡蛋白Bim上调SZ-685 C治疗与FOXO dephosphorylation.Conclusions和影响一致：SZ-685 C可以通过Akt/FOXO途径诱导细胞凋亡，从而导致观察到的抗肿瘤作用在体外和体内。我们的数据表明SZ-685 C可能是一种潜在的有希望的Akt抑制剂和抗癌候选药物。
Background and purpose:The aims of this study were to investigate the anti-cancer activity of SZ-685C, an anthracycline analogue isolated from marine-derived mangrove endophytic fungi, and to explore the molecular mechanisms underlying such activity.Experimental approach:The effect of SZ-685C on the viability of cancer cell lines was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. SZ-685C-induced apoptosis was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay and analysis of caspase activation. The effect of SZ-685C on the Akt/FOXO pathway was studied using Western blotting analysis, and the in vivo anti-tumour efficacy was examined in an MDA-MB-435 breast cancer xenograft model.Key results:SZ-685C suppressed the proliferation of six cancer cell lines derived from human breast cancer, prostate cancer, glioma and hepatoma (IC50 values ranged from 3.0 to 9.6 mu M) and the growth of breast cancer xenografts in mice. SZ-685C had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways, as shown by activation of caspase-8 and 9 as well as effector caspase-3 and poly (ADP-ribose) polymerase. Phosphorylation of Akt and its downstream effectors, forkhead box protein O1 and forkhead box protein O3a, was down-regulated in SZ-685C-treated cancer cells. Furthermore, the pro-apoptotic protein Bim was up-regulated by SZ-685C treatment consistent with FOXO dephosphorylation.Conclusions and implications:SZ-685C could induce apoptosis through the Akt/FOXO pathway, which consequently leads to the observed anti-tumour effect both in vitro and in vivo. Our data suggest that SZ-685C may be a potentially promising Akt inhibitor and anti-cancer drug candidate.