College of Life Science, Northwest Normal University, Lanzhou 730070, China.
Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730030, China.
Molecules. 2022 Aug 15;27(16):5191. doi: 10.3390/molecules27165191.
Derivates of natural products have been wildly utilized in the treatment of malignant tumors. Isorhamnetin (ISO), a most important active ingredient derived from flavonoids, shows great potential in tumor therapy. However, the therapeutic effects of ISO on gastric cancer (GC) remain unclear. Here, we demonstrate that ISO treatment dramatically inhibited the proliferation of two types of GC cells (AGS-1 and HGC-27) both in vitro and in vivo in time- and dose-dependent manners. These results are consistent with the transcriptomic analysis of ISO-treated GC cells, which yielded hundreds of differentially expressed genes that were enriched with cell growth and apoptosis. Mechanically, ISO treatment initiated the activation of caspase-3 cascade and elevated the expression of mitochondria-associated Bax/Bcl-2, cytosolic cytochrome c, followed by the activation of the cleavage of caspase-3 as well as poly ADP-ribose polymerase (PARP), resulting in the severe reduction of the mitochondrial potential and the accumulation of reactive oxygen species (ROS), while pre-treatment of the caspase-3 inhibitor could block the anti-tumor effect. Therefore, these results indicate that ISO treatment induces the apoptosis of GC cells through the mitochondria-dependent apoptotic pathway, providing a potential strategy for clinical GC therapy.
天然产物衍生物已被广泛应用于恶性肿瘤的治疗。山奈酚（ISO）是一种从类黄酮衍生而来的最重要的活性成分，在肿瘤治疗中具有巨大的潜力。然而，ISO 对胃癌（GC）的治疗效果尚不清楚。在这里，我们证明 ISO 处理在时间和剂量依赖性方式下，在体外和体内均能显著抑制两种 GC 细胞（AGS-1 和 HGC-27）的增殖。这些结果与 ISO 处理的 GC 细胞的转录组分析一致，产生了数百个差异表达的基因，这些基因富集了细胞生长和凋亡。从机制上讲，ISO 处理引发了 caspase-3 级联的激活，并提高了线粒体相关 Bax/Bcl-2、细胞质细胞色素 c 的表达，随后激活了 caspase-3 以及多聚 ADP-核糖聚合酶（PARP）的切割，导致线粒体电位严重降低和活性氧（ROS）的积累，而 caspase-3 抑制剂的预处理可以阻断抗肿瘤作用。因此，这些结果表明 ISO 处理通过线粒体依赖性凋亡途径诱导 GC 细胞凋亡，为临床 GC 治疗提供了一种潜在策略。
