Abstract Context Aaptamine is a potent ocean-derived non-traditional drug candidate against human cancers. However, the underlying molecular mechanisms governing aaptamine-mediated repression of lung cancer cells remain largely undefined. Objective To examine the inhibitory effect of aaptamine on proliferation and progression of non-small cell lung carcinoma (NSCLC) and dissect the potential mechanisms involved in its anticancer functions. Materials and methods In vitro assays of cell proliferation, cell cycle analysis, clonal formation, apoptosis and migration were performed to examine the inhibitory effects of aaptamine (8, 16 and 32 μg/mL) on NSCLC cells. The expression levels of proteins were analysed using western blotting analysis when cells were treated with a single drug or a combination treatment for 48 h. Results Aaptamine significantly inhibited A549 and H1299 cells proliferation with IC50 values of 13.91 and 10.47 μg/mL. At the concentrations of 16 and 32 μg/mL, aaptamine significantly reduced capacities in clonogenicity, enhanced cellular apoptosis and decreased the motile and invasive cellular phenotype. In addition, aaptamine arrested cell cycle at G1 phase via selectively abating cell cycle regulation drivers (CDK2/4 and Cyclin D1/E). Western blotting results showed that aaptamine attenuated the protein expression of MMP-7, MMP-9 and upregulated the expression of cleaved-PARP and cleaved-caspase 3. Moreover, aaptamine inhibited PI3K/AKT/GSK3β signalling cascades through specifically degrading the phosphorylated AKT and GSK3β. Discussion and conclusions Aaptamine retarded the proliferation and invasion of NSCLC cells by selectively targeting the pathway PI3K/AKT/GSK3β suggesting it as a potential chemotherapeutic agent for repressing tumorigenesis and progression of NSCLC in humans.

中文翻译：

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Aaptamine 减弱非小细胞肺癌的增殖和进展

摘要背景 Aaptamine 是一种有效的海洋衍生非传统候选药物，可用于对抗人类癌症。然而，控制 aaptamine 介导的肺癌细胞抑制的潜在分子机制在很大程度上仍未确定。目的探讨阿普他明对非小细胞肺癌（NSCLC）增殖和进展的抑制作用，剖析其抗癌作用的潜在机制。材料和方法 进行细胞增殖、细胞周期分析、克隆形成、细胞凋亡和迁移的体外测定，以检查 aaptamine（8、16 和 32 μg/mL）对 NSCLC 细胞的抑制作用。当细胞用单一药物或联合治疗处理 48 小时时，使用蛋白质印迹分析来分析蛋白质的表达水平。结果 Aaptamine 显着抑制 A549 和 H1299 细胞增殖，IC50 值为 13.91 和 10.47 μg/mL。在 16 和 32 μg/mL 的浓度下，aaptamine 显着降低了克隆形成能力，增强了细胞凋亡并降低了运动和侵袭性细胞表型。此外，aaptamine 通过选择性减弱细胞周期调节驱动因子（CDK2/4 和细胞周期蛋白 D1/E）在 G1 期阻滞细胞周期。蛋白质印迹结果显示，aaptamine 减弱 MMP-7、MMP-9 的蛋白表达并上调 cleaved-PARP 和 cleaved-caspase 3 的表达。此外，aaptamine 通过特异性降解磷酸化的 AKT 和GSK3β。