Chen Liubo, Jiang Kai, Chen Haiyan, Tang Yang, Zhou Xinyi, Tan Yinuo, Yuan Ying, Xiao Qian, Ding Kefeng
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,
Department of Surgical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China,
Cancer Manag Res. 2018 Dec 20;11:95-105. doi: 10.2147/CMAR.S169476. eCollection 2019.
Deguelin, a rotenoid extracted from (Leguminosae), exhibits antitumor effects on several types of human cancers. Due to the limited studies of deguelin on colorectal cancer (CRC), the present study was designed to investigate the antitumor effect of deguelin and to explore the underlying mechanism in CRC.
Cell viability was assessed by the cell counting kit-8 (CCK-8) assay, and cell apoptosis was determined by the annexin v-propidium iodide staining using flow cytometry and Western blot in CRC cell lines after incubation with deguelin. The antitumor effect of deguelin was further evaluated in tumor xenograft models. Moreover, SB203580, a specific inhibitor of p38 MAPK, was used to confirm the involvement of p38 MAPK pathway in deguelin-induced apoptosis.
Deguelin significantly inhibited cell proliferation and induced apoptosis in CRC cell lines (SW620 and RKO) in a time-dependent and dose-dependent manner. Western blot analysis also showed that the expression of proapoptotic proteins (cleaved caspase 3 and cleaved PARP) was upregulated, while that of antiapoptotic proteins (Bcl-2 and survivin) was downregulated after deguelin treatment in CRC cell lines. Moreover, oral administration of deguelin significantly suppressed tumor growth and induced apoptosis in subcutaneous xenograft mouse models without obvious toxicity. Additionally, Western blot revealed that deguelin-induced apoptosis might be regulated by the p38 MAPK pathway and inhibition of p38 MAPK could attenuate deguelin-induced proliferative inhibition and apoptosis in CRC cells.
Collectively, these results demonstrated that deguelin inhibited CRC cell growth by inducing apoptosis via activation of p38 MAPK pathway.
鱼藤素是从豆科植物中提取的一种鱼藤酮类化合物，对多种人类癌症具有抗肿瘤作用。由于关于鱼藤素对结直肠癌（CRC）的研究有限，本研究旨在探讨鱼藤素的抗肿瘤作用及其在CRC中的潜在作用机制。
使用细胞计数试剂盒-8（CCK-8）法评估细胞活力，通过膜联蛋白V-碘化丙啶染色结合流式细胞术和蛋白质免疫印迹法检测鱼藤素处理后的CRC细胞系中的细胞凋亡情况。在肿瘤异种移植模型中进一步评估鱼藤素的抗肿瘤作用。此外，使用p38丝裂原活化蛋白激酶（MAPK）的特异性抑制剂SB203580来确认p38 MAPK信号通路是否参与鱼藤素诱导的细胞凋亡。
鱼藤素以时间和剂量依赖性方式显著抑制CRC细胞系（SW620和RKO）的细胞增殖并诱导细胞凋亡。蛋白质免疫印迹分析还显示，在CRC细胞系中，经鱼藤素处理后，促凋亡蛋白（裂解的半胱天冬酶3和裂解的聚（ADP-核糖）聚合酶）的表达上调，而抗凋亡蛋白（Bcl-2和生存素）的表达下调。此外，口服鱼藤素可显著抑制皮下异种移植小鼠模型中的肿瘤生长并诱导细胞凋亡，且无明显毒性。另外，蛋白质免疫印迹显示，鱼藤素诱导的细胞凋亡可能受p38 MAPK信号通路调控，抑制p38 MAPK可减弱鱼藤素诱导的CRC细胞增殖抑制和细胞凋亡。
总体而言，这些结果表明鱼藤素通过激活p38 MAPK信号通路诱导细胞凋亡，从而抑制CRC细胞生长。
