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TNFα-related apoptosis inducing ligand (TRAIL) preferentially induces cancer cell death but spares normal cells, due partially to aberrant expression of death receptors (DR4 and DR5).TRAIL binds to its receptors DR4 and DR5, resulting in the activation of intrinsic and extrinsic apoptotic pathway.We investigated the expression pattern DR4 and DR5 in human liver cancer tissues, and evaluated TRAIL agonists as a novel treatment for liver cancer.Human liver cancer tissues were examined for DR expression by Western blot.Two humanized monoclonal antibodies (TRAIL agonists) for DR4 (HGS-ETR1) and DR5 (HGS-ETR2) were tested for anti-cancer activity using human liver cancer cell lines, both in vitro and in vivo using a xenograft mouse model.The TRAIL agonists were also tested in primary human hepatocyte culture to determine the toxicity.We found that more than 90% cancer tissues had more than 2-fold increases of DR5 expression compared with the corresponding non-cancer tissue.Both TRAIL agonists induced cancer cell apoptosis in cell culture.The LH86 cells were more sensitive than Huh7 cells (apoptotic index: 90% versus 7%).There was no overt apoptosis in normal primary hepatocyte cultures when these two TRAIL agonists were used.Moreover, the agonists, ETR1 and ETR2, significantly reduced the implanted tumor size in a xenograft mouse model.The tumor shrinkage was caused by apoptosis.There was no overt side effect during four weeks of treatment in the mice.Our study suggests that TRAIL apoptosis pathway can be activated by agonists, which is a novel approach to treat liver cancer.