细胞外囊泡递送甜菊醇衍生物治疗肾癌研究
首发时间:2026-05-08
摘要:肾癌是常见的泌尿系统恶性肿瘤,现有治疗手段存在耐药及毒副作用等问题。肿瘤坏死因子相关凋亡诱导配体(TRAIL)可选择性诱导肿瘤细胞凋亡,但重组TRAIL因肿瘤普遍存在的耐药性而临床应用受阻。前期研究证实,细胞外囊泡递送膜结合型TRAIL(EV-T)能显著增强TRAIL的抗癌活性。甜菊醇衍生物SD9是一种天然产物来源的化合物,可通过增加细胞内活性氧激活线粒体凋亡通路,具有TRAIL增敏潜力。本研究旨在探讨EV-T共载送TRAIL与SD9(SD9@EV-T)对肾癌细胞的杀伤效应及初步机制。通过超速离心法从过表达TRAIL的间充质干细胞培养上清中分离EV-T,超声法将SD9载入EV-T;选取肾癌细胞系(A498、Caki-1、786-O)及正常细胞MSC,通过CCK-8法检测细胞增殖活力;观察线粒体膜电位及细胞骨架形态变化。结果显示,SD9@EV-T显著抑制了肾癌细胞增殖,而对MSC无毒性;该制剂可降低A498细胞线粒体膜电位,并引起肌动蛋白解聚及细胞皱缩。综上,SD9@EV-T通过高效递送SD9并与TRAIL协同作用,激活线粒体凋亡通路,诱导肾癌细胞凋亡,为肾癌治疗提供了新策略。
关键词: 肾癌 甜菊醇衍生物 TRAIL耐药 EV-T 联合治疗
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Extracellular vesicle-mediated delivery of steviol derivatives for renal cell carcinoma therapy
Abstract:Renal cell carcinoma (RCC) is a common urinary system malignancy, and current treatments are limited by drug resistance and toxicity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells, but the clinical application of recombinant TRAIL has been hindered by the widespread drug resistance commonly observed in tumors. Previous studies have confirmed that extracellular vesicles delivering membrane-bound TRAIL (EV-T) significantly enhance the anticancer activity of TRAIL. Steviol derivative SD9, a compound derived from natural products, can activate the mitochondrial apoptosis pathway by increasing intracellular reactive oxygen species and possesses the potential to sensitize TRAIL. This study aims to investigate the cytotoxic effect and preliminary mechanism of extracellular vesicles co-delivering TRAIL and SD9 (SD9@EV-T) on renal cancer cells.EV-T was isolated from the culture supernatant of TRAIL-overexpressing mesenchymal stem cells by ultracentrifugation, followed by loading of SD9 into EV-T using an ultrasonic method. The proliferation viability of renal cancer cell lines (A498, Caki-1, 786-O) and normal MSCs was evaluated by the CCK-8 assay. Changes in mitochondrial membrane potential and cytoskeletal morphology were observed. Results showed that SD9@EV-T significantly inhibited RCC cell proliferation without toxicity to MSCs. Moreover, SD9@EV-T reduced mitochondrial membrane potential in A498 cells and induced actin depolymerization and cell shrinkage. In conclusion,SD9@EV-T efficiently delivers SD9 and exerts a synergistic effect with TRAIL, thereby activating the mitochondrial apoptotic pathway and inducing apoptosis in renal cancer cells, offering a novel therapeutic strategy for renal cancer.
Keywords: Renal cell carcinoma Steviol derivative TRAIL resistance;EV-T Combination therapy
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细胞外囊泡递送甜菊醇衍生物治疗肾癌研究
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