Synergistic interaction between Parthenolide and TRAIL induces apoptosis in human hepatocarcinoma cells.

Partenolide, a natural compound used in traditional medicine for its anti-inflammatory activity, has recently shown anti-tumor and apoptotic effects. Our studies demonstrated that HepG2; Hep3B and SK-Hep1 hepatocarcinoma cells, which are resistant to human recombinant TRAIL, are potently sensitized to TRAIL-induced apoptosis by low doses of parthenolide resulting in a marked synergist effect. To clarify the mechanism that accounts for this interaction, we demonstrated that parthenolide/TRAIL combination markedly increased DR4 and DR5. These effects might be correlated with STAT proteins modifications. In fact parthenolide and parthenolide/TRAIL combination decreased STAT3 and STAT5 and their phosphorylated forms. These lowering effects could be responsible for increased expression of death receptors, as suggested by the observation that down-regulation of STAT proteins by siRNA, stimulated the expression of both DR4 and DR5. Although the anti-tumor activity of parthenolide was identified recently, this research area appears promising as it is likely that parthenolide/TRAIL combination may contribute to the rational design of novel targeted therapies.