HY-1 induces G(2)/M cell cycle arrest in human colon cancer cells through the ATR-Chk1-Cdc25C and Weel pathways

Cancer Sci. 2013 Aug;104(8):1062-6. doi: 10.1111/cas.12182. Epub 2013 May 15.

Abstract

The novel aroylthiourea analogue of podophyllotoxin HY-1 (4β-[benzoyl-thioureido]-4-deoxypodophyllotoxin) was synthesized in our laboratory with the aim of developing multitargeted DNA topoisomerase II inhibitors. The compound showed significant antiproliferative effects on seven cancer cell lines and induced G2 /M phase arrest in HCT116 cells. Moreover, HY-1 showed a potent inhibitory effect on topoisomerase II-mediated kinetoplast DNA decatenation in a dose-dependent manner. Our results showed that cdc2 phosphorylation and decreased cdc2 kinase acitivity through the ATR-Chk1-Cdc25C and Weel pathways were the central mechanisms for G2 /M phase arrest in human colon cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Division / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Checkpoint Kinase 1
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism
  • DNA, Kinetoplast / genetics
  • G2 Phase / drug effects*
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • HCT116 Cells
  • Hep G2 Cells
  • Humans
  • KB Cells
  • Mice
  • Phosphorylation / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Topoisomerase II Inhibitors / pharmacology
  • cdc25 Phosphatases / genetics
  • cdc25 Phosphatases / metabolism*

Substances

  • DNA, Kinetoplast
  • Topoisomerase II Inhibitors
  • N-phthalylglycine dimethylamide
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • CDC2 Protein Kinase
  • CDC25C protein, human
  • cdc25 Phosphatases
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • Glycine