Varjavand Kesht Kariman Co., Ltd, Kerman, Iran; Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran.
Department of Computer Engineering, Faculty of Engineering, Ferdowsi University of Mashhad, Mashhad, Iran; Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Chem Biol Interact. 2023 Sep 1;382:110642. doi: 10.1016/j.cbi.2023.110642. Epub 2023 Jul 23.
The polyphenolic component of citrus fruits, hesperetin (Hst), is a metabolite of hesperidin. In this study, we examined the effect of varying doses and exposure times of hesperetin on MCF-7 and MDA-MB-231 cancer cells, as well as MCF-10A normal cells. By using MTT assay, real-time PCR, western blot, and flow cytometry, we determined the effects of Hst on cell viability, ROS levels, and markers of cell death. Furthermore, molecular docking was used to identify Hst targets that might be involved in ROS-dependent cell death. According to the results, different concentrations of Hst induced different modes of cell death at specific ROS levels. Paraptosis occurred in all cell lines at concentration ranges of IC to IC, and apoptosis occurred at concentrations greater than IC. In addition, MDA-MB-231 cells were subjected to senescence at sub-toxic doses when treated for a long period of time. When Hst levels were higher, N-acetylcysteine (NAC)'s effect on neutralizing ROS was more pronounced. According to the docking results, Hst may interact with several proteins involved in the regulation of ROS. As an example, the interaction of CCS (Copper chaperone for superoxide dismutase) with Hst might interfere with its chaperone function in folding SOD-1 (superoxide dismutase enzyme), contributing to an increase in cytoplasmic ROS levels. Finally, depending on the ROS level, Hst induces various modes of cell death.
柑橘类水果中的多酚成分，橙皮苷素（Hst），是橙皮苷的代谢物。在这项研究中，我们研究了不同剂量和暴露时间的橙皮苷素对 MCF-7 和 MDA-MB-231 癌细胞以及 MCF-10A 正常细胞的影响。通过 MTT 测定法、实时 PCR、western blot 和流式细胞术，我们确定了 Hst 对细胞活力、ROS 水平和细胞死亡标志物的影响。此外，还使用分子对接来鉴定可能参与 ROS 依赖性细胞死亡的 Hst 靶标。结果表明，不同浓度的 Hst 在特定的 ROS 水平下诱导不同模式的细胞死亡。在所有细胞系中，IC 至 IC 浓度范围内发生 Paraptosis，IC 以上浓度发生凋亡。此外，MDA-MB-231 细胞在长时间低毒性剂量处理下发生衰老。当 Hst 水平较高时，N-乙酰半胱氨酸（NAC）对中和 ROS 的作用更加明显。根据对接结果，Hst 可能与参与 ROS 调节的几种蛋白质相互作用。例如，CCS（超氧化物歧化酶的铜伴侣）与 Hst 的相互作用可能干扰其在折叠 SOD-1（超氧化物歧化酶酶）中的伴侣功能，导致细胞质 ROS 水平升高。最后，根据 ROS 水平的不同，Hst 诱导不同的细胞死亡模式。
