Anti-angiogenic and anti-tumor apoptotic activities of SJ-8002, a new piperazine derivative

Int J Oncol. 2004 Aug;25(2):365-72.

Abstract

A new piperazine derivative, SJ-8002, is a synthetic anti-cancer agent which exhibits microtubule-inhibiting activities. In this study, we investigated the possibility that this compound inhibits angiogenesis and induces tumor-cell apoptosis using bovine aortic endothelial cells (BAECs) and human hepatocellular carcinoma cells (HepG2) as a model system, respectively. In vivo, SJ-8002 decreased the neovascularization of chick embryos and the basic fibroblast growth factor (bFGF)-induced angiogenesis in the chorioallantoic membrane (CAM) and the mouse Matrigel implants, respectively. In vitro, SJ-8002 treatment resulted in the inhibition of proliferation, migration, invasion and tube formation, and of matrix metalloproteinase-2 (MMP-2) expression in BAECs. In addition, the SJ-8002 treatment in HepG2 cells reduced cell viability, and caused the production of fragmented DNA and the morphological changes corresponding to apoptosis including condensed and fragmented DNA in a concentration-dependent manner. SJ-8002 also elicited the release of cytochrome c and the activation of caspase-3. Therefore, it is possible that SJ-8002 functions as both angiogenesis inhibitor and apoptosis inducer. Taken together, these results suggest that SJ-8002 may be a candidate for strong anti-cancer agent with the ability to inhibit the angiogenesis of endothelial cells and to induce the apoptosis of tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • Biological Assay
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chick Embryo
  • Collagen / drug effects
  • Cytochromes c / metabolism
  • Drug Combinations
  • Laminin / drug effects
  • Matrix Metalloproteinase 2 / drug effects
  • Mice
  • Neoplasms / drug therapy
  • Neovascularization, Pathologic / drug therapy
  • Piperazine
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Proteoglycans / drug effects

Substances

  • 4-(3,5-dimethylphenyl)piperazine-1-carboxylic acid (2-methoxy-5,6-dimethylpyridin-3-yl)amide
  • Aminopyridines
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Drug Combinations
  • Laminin
  • Piperazines
  • Proteoglycans
  • matrigel
  • Piperazine
  • Collagen
  • Cytochromes c
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Matrix Metalloproteinase 2