Department of Urology, The First Affiliated Hospital, China Medical University, Shenyang, China.
Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, China.
J Cell Biochem. 2018 Nov;119(10):8611-8622. doi: 10.1002/jcb.27116. Epub 2018 Jun 20.
Betulinic acid (BA), a natural product with a broad range of biological properties, is a lupane-type pentacyclic triterpene isolated from various plants. Evidence is accumulating that BA is cytotoxic against multiple types of human cancer cells; however, its effects on renal carcinoma cells remain obscure. This study aimed to evaluate the anticancer activity of BA in human renal cancer cells in vitro and in vivo. In the current study, we found that BA inhibited renal cancer cell proliferation in a time-dependent and dose-dependent manner in vitro. Moreover, flow cytometry analysis revealed that BA affected the survival of renal cancer cells via the induction of apoptosis. Western blot analysis showed that the occurrence of apoptosis was associated with upregulation of Bcl2-associated X protein and cleaved caspase-3 and downregulation of B-cell lymphoma 2 in renal cancer cells. Additionally, BA treatment augmented the production of reactive oxygen species and induced a significant loss of mitochondrial membrane potential in renal cancer cells, suggesting that BA may trigger apoptosis via the mitochondria-mediated apoptotic pathway. Furthermore, the migrative and invasive capabilities of renal cancer cells were markedly repressed by BA treatment, which was related to upregulation of matrix metalloproteinase (MMP)2, MMP9, and vimentin, and downregulation of tissue inhibitor of metalloproteinase 2 and E-cadherin. Notably, administration of BA retarded tumor growth in 786-O-bearing mice in vivo. Taken together, our results demonstrated the anticancer potential of BA in human renal cancer cells by triggering apoptosis and suppressing migration and invasion.
白桦脂酸 (BA) 是一种具有广泛生物学特性的天然产物，是一种从多种植物中分离出来的羽扇豆烷型五环三萜。有证据表明，BA 对多种类型的人类癌细胞具有细胞毒性；然而，其对肾癌细胞的影响尚不清楚。本研究旨在评估 BA 在体外和体内对人肾癌细胞的抗癌活性。在本研究中，我们发现 BA 以时间和剂量依赖的方式抑制体外肾癌细胞的增殖。此外，流式细胞术分析显示，BA 通过诱导细胞凋亡影响肾癌细胞的存活。Western blot 分析表明，细胞凋亡的发生与 Bcl2 相关 X 蛋白和 cleaved caspase-3 的上调以及 B 细胞淋巴瘤 2 的下调有关。此外，BA 处理增加了肾癌细胞中活性氧的产生，并诱导线粒体膜电位显著丧失，表明 BA 可能通过线粒体介导的凋亡途径引发细胞凋亡。此外，BA 处理显著抑制肾癌细胞的迁移和侵袭能力，这与基质金属蛋白酶 (MMP)2、MMP9 和波形蛋白的上调以及组织金属蛋白酶抑制剂 2 和 E-钙黏蛋白的下调有关。值得注意的是，BA 的给药在体内抑制了 786-O 荷瘤小鼠的肿瘤生长。综上所述，我们的研究结果表明，BA 通过触发细胞凋亡和抑制迁移和侵袭，具有抑制人肾癌细胞生长的抗癌潜力。
