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

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.

• Authors: Yajie Wang, Hua Sun, Zhiyan Xiao, Gang Zhang, Dan Zhang, Xiuqi Bao, Fangfang Li, Shaoyu Wu, Yuanchao Gao, Ning Wei
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 16 Issue 1 Pg. 52 (09 03 2018) ISSN: 1478-811X [Electronic] England
• PMID: 30176902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Poly-ADP-Ribose Binding Proteins
• Reactive Oxygen Species
• Proto-Oncogene Proteins c-mdm2
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• DNA Topoisomerases, Type II
• TOP2A protein, human
• Podophyllotoxin

Topics

• Administration, Oral
• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• DNA Damage
• DNA Topoisomerases, Type II (chemistry, metabolism)
• Female
• Humans
• MCF-7 Cells
• Mice
• Molecular Docking Simulation
• Phosphatidylinositol 3-Kinases (metabolism)
• Podophyllotoxin (administration & dosage, analogs & derivatives, metabolism, pharmacology)
• Poly-ADP-Ribose Binding Proteins (chemistry, metabolism)
• Protein Conformation
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays