Li Hongfang, Deng Changfeng, Zhu Neng, Zhang Chanjuan, Zeng Qing, Qin Li
Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, Hunan University of Chinese Medicine, Changsha 410208, China.
Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China.
Bioorg Chem. 2023 May;134:106454. doi: 10.1016/j.bioorg.2023.106454. Epub 2023 Mar 4.
Glutathione (GSH) is closely related to the occurrence and development of tumors. The intracellular GSH levels are abnormally altered when tumor cells undergo programmed cell death. Therefore, real-time monitoring of the dynamic changes of intracellular GSH levels can better enable the early diagnosis of diseases and evaluate the effects of cell death-inducing drugs. In this study, a stable and highly selective fluorescent probe AR has been designed and synthesized for the fluorescence imaging and rapid detection of GSH in vitro and in vivo, as well as patient-derived tumor tissue. More importantly, the AR probe can be used to track changes in GSH levels and fluorescence imaging during the treatment of clear cell renal cell carcinoma (ccRCC) with celastrol (CeT) via inducing ferroptosis. These findings demonstrate that the developed fluorescent probe AR exhibits high selectivity and sensitivity, as well as good biocompatibility and long-term stability, which can be used to image endogenous GSH in living tumors and cells. Also, a significant decrease in GSH levels was observed by the fluorescent probe AR during the treatment of ccRCC with CeT-induced ferroptosis in vitro and in vivo. Overall, these findings will provide a novel strategy for celastrol targeting ferroptosis in the treatment of ccRCC and the application of fluorescent probes to help reveal the underlying mechanism of CeT in the treatment of ccRCC.
谷胱甘肽（GSH）与肿瘤的发生发展密切相关。当肿瘤细胞发生程序性细胞死亡时，细胞内GSH水平会发生异常改变。因此，实时监测细胞内GSH水平的动态变化能够更好地实现疾病的早期诊断，并评估诱导细胞死亡药物的效果。在本研究中，设计并合成了一种稳定且具有高选择性的荧光探针AR，用于体外、体内以及患者来源的肿瘤组织中GSH的荧光成像和快速检测。更重要的是，AR探针可用于通过诱导铁死亡，在使用雷公藤红素（CeT）治疗透明细胞肾细胞癌（ccRCC）过程中追踪GSH水平变化及进行荧光成像。这些发现表明，所开发的荧光探针AR具有高选择性和灵敏度，以及良好的生物相容性和长期稳定性，可用于对活体内肿瘤和细胞中的内源性GSH进行成像。此外，在体外和体内使用CeT诱导铁死亡治疗ccRCC过程中，荧光探针AR观察到GSH水平显著下降。总体而言，这些发现将为雷公藤红素靶向铁死亡治疗ccRCC以及荧光探针的应用提供一种新策略，以帮助揭示CeT治疗ccRCC的潜在机制。
