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, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Sci Rep. 2017 Aug 30;7(1):9989. doi: 10.1038/s41598-017-10577-7.
A novel podophyllotoxin derivative, XWL-1-48, was synthesized as an oral topoisomerase II inhibitor. kDNA decatenation assay indicated that XWL-1-48 significantly inhibited topoisomerase II activity in a concentration-dependent manner. Moreover, the cytotoxicity of XWL-1-48 is more potent than its congener GL331 and the IC values are from 0.34 ± 0.21 to 3.54 ± 0.54 µM in 10 cancer cell lines including KBV200 cells with P-gp overexpression. Noticeably, XWL-1-48 exerted potent antitumor activity in in vitro and in vivo human hepatocellular carcinoma (HCC) model. Further studies demonstrated that treatment of XWL-1-48 induced γ-H2AX and p-ATM expression, and further triggered DNA damage response through activation of ATM-p53-p21 and ATM-Chk2-Cdc25A pathways. Targeted inhibition of ATM by siRNA attenuated the ability of XWL-1-48 on inducing DNA damage. XWL-1-48 significantly suppressed Cyclin A and p-Cdk2 (Thr160) expression, increased p-Cdk2 (Thr14), led to inactivation of Cyclin A/Cdk2 complex, arrested cell cycle at S phase. Finally, XWL-1-48 elevated the ratio of Bax/Bcl2 and induced Fas and FasL, initiated mitochondria- and death receptor-mediated apoptosis pathway. Meanwhile, XWL-1-48 evidently enhanced degradation of Mdm2, blocked PI3K/Akt/Mdm2 pathway and suppressed HCC cell survival. Thus, XWL-1-48 may be a promising orally topoisomerase II inhibitor for treatment of HCC.
一种新型鬼臼毒素衍生物 XWL-1-48 被合成作为一种口服拓扑异构酶 II 抑制剂。kDNA 解连环实验表明，XWL-1-48 以浓度依赖性方式显著抑制拓扑异构酶 II 活性。此外，XWL-1-48 的细胞毒性比其同类物 GL331 更强，在包括 P-糖蛋白过表达的 KBV200 细胞在内的 10 种癌细胞系中的 IC 值为 0.34±0.21 至 3.54±0.54μM。值得注意的是，XWL-1-48 在体外和体内人肝癌（HCC）模型中均显示出强大的抗肿瘤活性。进一步的研究表明，XWL-1-48 处理诱导 γ-H2AX 和 p-ATM 表达，并通过激活 ATM-p53-p21 和 ATM-Chk2-Cdc25A 通路进一步引发 DNA 损伤反应。siRNA 靶向抑制 ATM 减弱了 XWL-1-48 诱导 DNA 损伤的能力。XWL-1-48 显著抑制 Cyclin A 和 p-Cdk2（Thr160）表达，增加 p-Cdk2（Thr14），导致 Cyclin A/Cdk2 复合物失活，细胞周期停滞在 S 期。最后，XWL-1-48 提高了 Bax/Bcl2 的比值，并诱导 Fas 和 FasL，启动线粒体和死亡受体介导的凋亡途径。同时，XWL-1-48 明显增强了 Mdm2 的降解，阻断了 PI3K/Akt/Mdm2 通路，并抑制了 HCC 细胞的存活。因此，XWL-1-48 可能是一种有前途的口服拓扑异构酶 II 抑制剂，可用于治疗 HCC。
