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XWL-1-48 exerts antitumor activity via targeting topoisomerase II and enhancing degradation of Mdm2 in human hepatocellular carcinoma
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 c...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577045/ https://www.ncbi.nlm.nih.gov/pubmed/28855652 http://dx.doi.org/10.1038/s41598-017-10577-7 |
Sumario: | 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(50) 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. |
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