DNA damage and apoptosis induced by a potent orally podophyllotoxin derivative in breast cancer

Yajie Wang, Hua Sun, Zhiyan Xiao, Gang Zhang, Dan Zhang, Xiuqi Bao, Fangfang Li, Shaoyu Wu, Yuanchao Gao, Ning Wei

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Article number52
JournalCell Communication and Signaling
Volume16
Issue number1
DOIs
StatePublished - Sep 3 2018
Externally publishedYes

Keywords

  • Breast cancer
  • DNA damage
  • Mdm2
  • p53
  • TopoisomeraseII

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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