Department of Pharmacognosy, College of Pharmacy, Cairo University , Giza 11562, Egypt.
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University , Ulm D-89081, Germany.
J Nat Prod. 2017 Dec 22;80(12):3203-3210. doi: 10.1021/acs.jnatprod.7b00546. Epub 2017 Nov 30.
We investigated the cytotoxic potential of the cardenolide glycoside acovenoside A against non-small-cell lung cancer cells. Lung cancer is the leading cause of cancer-related mortality and the second most common cancer diagnosed. Epidemiological studies revealed a direct correlation between the regular administration of cardiac glycosides and a lower incidence of various cancers. Acovenoside A, isolated from the pericarps of Acokanthera oppositifolia, potently inhibited proliferation and induced cytotoxicity in A549 non-small-cell lung cancer cells with an IC of 68 ± 3 nM after 48 h of exposure. Compared to the antineoplastic agent doxorubicin, acovenoside A was more potent in inhibiting the viability of A549 cancer cells. Moreover, acovenoside A exhibited selectivity against cancer cells, being significantly less toxic to lung fibroblasts and nontoxic for peripheral blood mononuclear cells. Analysis of the cell cycle profile in acovenoside A-treated A549 cells revealed mitotic arrest, due to accumulation of the G/M regulators cyclin B and CDK1, and cytokinesis failure. Furthermore, acovenoside A affected the mitochondrial membrane integrity and induced production of radical oxygen species, which resulted in induction of canonical apoptosis, manifested by caspase 3 activation and DNA fragmentation. Based on our results, acovenoside A warrants further exploration as a potential anticancer lead.
我们研究了卡烯醇苷糖苷 acovenoside A 对非小细胞肺癌细胞的细胞毒性潜力。肺癌是癌症相关死亡的主要原因，也是第二大常见的癌症诊断。流行病学研究表明，定期给予强心苷与各种癌症发病率降低之间存在直接相关性。从 Acokanthera oppositifolia 的果皮中分离得到的 acovenoside A，在暴露 48 小时后，对 A549 非小细胞肺癌细胞的增殖具有强烈的抑制作用，IC 为 68 ± 3 nM，并诱导细胞毒性。与抗肿瘤药物阿霉素相比，acovenoside A 更能抑制 A549 癌细胞的活力。此外，acovenoside A 对癌细胞具有选择性，对肺成纤维细胞的毒性明显较小，对外周血单个核细胞也没有毒性。在 acovenoside A 处理的 A549 细胞中分析细胞周期谱时发现有丝分裂阻滞，这是由于 G/M 调节因子 cyclin B 和 CDK1 的积累以及胞质分裂失败所致。此外，acovenoside A 影响线粒体膜的完整性并诱导活性氧的产生，从而导致经典的细胞凋亡，表现为 caspase 3 的激活和 DNA 片段化。基于我们的结果，acovenoside A 值得进一步探索作为一种潜在的抗癌先导化合物。
