双吲哚生物碱是新一代抗癌剂设计和发现的灵感来源。在这项研究中,我们研究了来自传统抗癌菲律宾药用植物Voacangaglobosa的三种spirobisindle生物碱的细胞毒性和抗增殖活性,以及他们的行动机制。因此,生物碱球形螺旋胺(1),脱氧伏特宁(2),和vobtusine内酯(3)使用MTT和CellTiter-Blue测定法显示出对测试细胞系(L929,KB3.1,A431,MCF-7,A549,PC-3和SKOV-3)的体外细胞毒性和抗增殖活性。还使用磺基罗丹明B(SRB)测定法针对一组乳腺癌细胞系筛选了环螺胺(1),并显示出中等的细胞毒性。它还使用Caspase-Glo3/7和CellEvent-3/7凋亡测定促进凋亡效应子caspase3和7的激活。还观察到用1处理的A549细胞中裂解的半胱天冬酶3和PARP的表达增加。根据HeLa细胞膜通透性测定,当球形螺旋胺(1)未能促进膜完整性的快速丧失时,也证实了凋亡活性。网络药理学分析,分子对接,和分子动力学模拟确定了MAPK14(p38α),导致癌细胞凋亡的药理靶点,作为假定的目标。低毒性风险和良好的药物相似性也被预测为1。总的来说,我们的研究证明了球形螺旋胺的抗癌潜力和凋亡机制(1),验证Voacangaglobosa的传统药用。
Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant Voacanga globosa, along with their mechanisms of action. Thus, the alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.1, A431, MCF-7, A549, PC-3, and SKOV-3) using MTT and CellTiter-Blue assays. Globospiramine (1) was also screened against a panel of breast cancer cell lines using the sulforhodamine B (SRB) assay and showed moderate cytotoxicity. It also promoted the activation of apoptotic effector caspases 3 and 7 using Caspase-Glo 3/7 and CellEvent-3/7 apoptosis assays. Increased expressions of cleaved caspase 3 and PARP in A549 cells treated with 1 were also observed. Apoptotic activity was also confirmed when globospiramine (1) failed to promote the rapid loss of membrane integrity according to the HeLa cell membrane permeability assay. Network pharmacology analysis, molecular docking, and molecular dynamics simulations identified MAPK14 (p38α), a pharmacological target leading to cancer cell apoptosis, as a putative target. Low toxicity risks and favorable drug-likeness were also predicted for 1. Overall, our study demonstrated the anticancer potentials and apoptotic mechanisms of globospiramine (1), validating the traditional medicinal use of Voacanga globosa.