This article shows that HepG2, Hep3B, and SK-Hep1 cells, three lines of human hepatocellular carcinoma (HCC) cells, are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Parthenolide, a sesquiterpene lactone found in European feverfew, has been shown to exert both anti-inflammatory and anti-cancer activities. This article demonstrates that co-treatment with parthenolide and TRAIL-induced apoptosis with synergistic interactions in the three lines of HCC cells. In order to explain these effects we ascertained that parthenolide increased either at protein or mRNA level the total content of death receptors TRAIL-R1 and -R2 as well as their surface expression. These effects were found in the three cell lines in the case of TRAIL-R2, while for TRAIL-R1 they were observed in HepG2 and SK-Hep1 cells, but not in Hep3B cells. We suggest that the effects of parthenolide on death receptors depend on the decrease in the level of phosphorylated and active forms of STAT proteins, an event which could be a consequence of the inhibitory effect exerted by parthenolide on the activation of JAK proteins. In agreement with this hypothesis treatment with STAT3 siRNA increased in HCC cells the effect of parthenolide on the expression of death receptors. Sensitization by parthenolide to TRAIL stimulated in the three cell lines the extrinsic mechanism of apoptosis with the activation of both caspases 8 and 3, whereas mitochondria were not involved in the process. Our results suggest that co-treatment with parthenolide and TRAIL could represent a new important therapeutic strategy for hepatic tumors.

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