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

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

doi:10.1186/s12964-018-0263-9

Abstract

BackgroundTargeting 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.MethodsXWL-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.ResultsThe 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.ConclusionXWL-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.

Highlights

Targeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer
Effect of XWL-1-48 on TopoII activity and growth of breast cancer cells TopoII is well validated as a target of anticancer drugs, and some agents targeting to TopoII are currently used clinically for treatment of various types of cancer
Based on the chemical structure of XWL-1-48, we firstly evaluated the ability of XWL-1-48 binding to TopoII by using molecular docking software

Summary

Introduction

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. Much progress has been made in breast cancer treatment, there are remaining some barriers to cure for breast cancer, including intratumor genomic heterogeneity, Noticeably, targeted DNA damage and DNA repair is a successful strategy for treatment of breast cancer. TopoisomeraseII (TopoII) is known as a validated target for drug discovery and cancer chemotherapy. The DNA TopoII plays a key role in the process of transcription, replication, and chromosome segregation [7]. TopoIIα is essential for the proliferation of growing cells and able to decatenate the replicated chromosomes during the process of chromosome segregation [8]. The expression level of TopoIIα is significantly upregulated during cell proliferation.

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