Li Xiaolan, He Songhua, Liang Wei, Zhang Weiquan, Chen Xin, Li Qiaofeng, Yang Xin, Liu Yanying, Zhu Dan, Li Li, Liu Buming, Su Zhiheng, Chen Jie, Guo Hongwei
Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & College of Pharmacy, Guangxi Medical University, Nanning 530021, China; Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education & Center for Translational Medicine, Guangxi Medical University, Nanning 530021, China.
Guangxi Institute for Food and Drug Control, Drug Administration of Zhuang Autonomous Region, Nanning 530021, China.
Chin J Nat Med. 2023 Feb;21(2):113-126. doi: 10.1016/S1875-5364(23)60389-9.
Marsdenia tenacissima injection, a standard Marsdenia tenacissima extract (MTE), has been approved as an adjuvant therapeutic agent for various cancers. Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer (PCa) cells. However, the underlying mechanisms and active ingredients of MTE against PCa were not completely understood. This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells. In addition, MTE induced the apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7, Cyt c, and Bax. In vivo, DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size. TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE. Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets, and 709 PCa-associated targets were retrieved, from which 149 overlapped targets were screened out. Pathway enrichment analysis showed that the HIF-1, PI3K-AKT, and ErbB signaling pathways were closely related to tumor apoptosis. Western blot results confirmed that MTE increased the expression of p-AKT and p-GSK3β, and decreased the expression of p-STAT3in vitro and in vivo. A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLC-QTOF-MS/MS. Molecular docking analysis indicated that six compounds may interact with AKT, GSK3β, and STAT3. In conclusion, MTE induces the endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3β/STAT3 signaling axis, resulting in inhibition of PCa growth in vitro and in vivo.
通关藤注射液，一种标准的通关藤提取物（MTE），已被批准作为多种癌症的辅助治疗药物。我们之前的研究表明，MTE可抑制前列腺癌细胞（PCa）的增殖和转移。然而，MTE抗PCa的潜在机制和活性成分尚未完全明确。本研究表明，MTE可导致PCa细胞的活力和克隆生长显著降低。此外，MTE通过降低线粒体膜电位、增加Cleaved Caspase 3/7、Cyt c和Bax的表达来诱导DU145细胞凋亡。在体内，用MTE处理的DU145异种移植NOD-SCID小鼠的肿瘤大小显著减小。TUNEL染色和蛋白质印迹证实了MTE的促凋亡作用。网络药理学分析收集了与655个潜在靶点相关的196种MTE成分，并检索到709个PCa相关靶点，从中筛选出149个重叠靶点。通路富集分析表明，HIF-1、PI3K-AKT和ErbB信号通路与肿瘤凋亡密切相关。蛋白质印迹结果证实，MTE在体外和体内均可增加p-AKT和p-GSK3β的表达，并降低p-STAT3的表达。通过HPLC-CAD-QTOF-MS/MS和UPLC-QTOF-MS/MS共鉴定出MTE中的13种化合物。分子对接分析表明，六种化合物可能与AKT、GSK3β和STAT3相互作用。总之，MTE通过调节AKT/GSKβ/STAT3信号轴诱导PCa的内源性线粒体凋亡，从而在体外和体内抑制PCa的生长。
