State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Cell Commun Signal. 2018 Sep 3;16(1):52. doi: 10.1186/s12964-018-0263-9.
Targeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. TopoII is known as a validated target for drug discovery and cancer chemotherapy.
XWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on TopoII binding and activity was determined by molecular docking software and kDNA-decatenation assay, respectively. In vitro and in vivo breast cancer models were used to document the antitumor activity of XWL-1-48. Cellular apoptosis, cell cycle and ROS were analyzed by flow cytometry. Alteration of XWL-1-48-mediated downstream pathways was determined by western blot analysis.
The cytotoxicity of XWL-1-48 is more potent than that of its congener GL331. Molecular docking demonstrated that XWL-1-48 could bind to TopoII through forming two strong hydrogen bonds and potential pi-pi interactions. Noticeably, XWL-1-48 exerts potent antitumor activity in in vitro and in vivo breast cancer model. Treatment with XWL-1-48 caused ROS generation and triggered DNA damage through induction of γ-H2AX and activation of ATM/p53/p21 pathway. Further studies showed that XWL-1-48 led to S-phase arrest and mitochondrial apoptosis. Meanwhile, XWL-1-48 significantly blocked PI3K/Akt/Mdm2 pathway and enhanced Mdm2 degradation.
XWL-1-48 may be a promising orally topoII inhibitor, its mechanisms are associated with suppression of TopoII, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.
靶向拓扑异构酶 II（TopoII）并产生酶介导的 DNA 损伤是治疗乳腺癌的有效策略。TopoII 是药物发现和癌症化疗的有效靶点。
设计并合成了一种新型的口服鬼臼毒素衍生物 XWL-1-48。分别通过分子对接软件和 kDNA 解连环试验测定 XWL-1-48 对 TopoII 结合和活性的影响。使用体外和体内乳腺癌模型来记录 XWL-1-48 的抗肿瘤活性。通过流式细胞术分析细胞凋亡、细胞周期和 ROS。通过 Western blot 分析测定 XWL-1-48 介导的下游途径的改变。
XWL-1-48 的细胞毒性比其同系物 GL331 更强。分子对接表明，XWL-1-48 可以通过形成两个强氢键和潜在的 pi-pi 相互作用与 TopoII 结合。值得注意的是，XWL-1-48 在体外和体内乳腺癌模型中均具有强大的抗肿瘤活性。XWL-1-48 处理会引起 ROS 生成，并通过诱导 γ-H2AX 和激活 ATM/p53/p21 途径引发 DNA 损伤。进一步的研究表明，XWL-1-48 导致 S 期停滞和线粒体凋亡。同时，XWL-1-48 显著阻断了 PI3K/Akt/Mdm2 途径并增强了 Mdm2 的降解。
XWL-1-48 可能是一种有前途的口服拓扑异构酶 II 抑制剂，其机制与抑制 TopoII、诱导 DNA 损伤和凋亡、阻断 PI3K/AKT/Mdm2 途径有关。
