Anti-proliferative activity of fenretinide in human hepatoma cells in vitro and in vivo

Anticancer Drugs. 2007 Jan;18(1):47-53. doi: 10.1097/CAD.0b013e32800feeb5.

Abstract

N-(4-hydroxyphenyl)-retinamide (fenretinide) is a synthetic derivative of all-trans-retinoic acid and induces apoptosis in several cancer cell lines. We determined the anti-cancer activity of fenretinide using human hepatoma cell lines, Bel-7402, HepG2 and Smmc-7721. An in-vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that fenretinide exhibited growth inhibition in these cell lines, with IC50 values ranging from 13.1 to 15.5 micromol/l. In Bel-7402 cells, apoptosis with 15 micromol/l fenretinide for 0 and 48 h was 3 and 48%, respectively. In-vivo studies using the Bel-7402 xenografted athymic mouse model showed tumor inhibition rates ranging from 37.2 to 57.2%, with fenretinide administration once per 3 days at the rate of 25-100 mg/kg. Western blot analysis further showed down-regulation of procaspase-3, X-linked inhibitor of apoptosis protein and poly(ADP-ribose) polymerase cleavage in Bel-7402 cells treated with 15 mumol/l fenretinide for 48 h. Overexpression of p53 was observed in a time-dependent manner, along with a decrease in the Bcl-2/Bax ratio. Depolarized mitochondrial membranes were found in fenretinide-induced apoptotic cells, in a time-dependent manner. We conclude that fenretinide effectively inhibits the proliferation of Bel-7402, both in vitro and in vivo. Both procaspase-3 and p53-mediated apoptotic pathways are involved in its potent anti-cancer activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Carcinoma, Hepatocellular / drug therapy
  • Cell Proliferation / drug effects
  • Fenretinide / pharmacology*
  • Fenretinide / therapeutic use
  • Flow Cytometry
  • Humans
  • In Vitro Techniques
  • Liver Neoplasms / drug therapy
  • Membrane Potentials / drug effects
  • Mice
  • Models, Biological*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Fenretinide