Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is a potential
biological anticancer agent. However, a wide range of human primary
cancers, including
pancreatic cancer, display resistance to apoptosis induction by TRAIL. Therefore, this resistance needs to be overcome to allow TRAIL to be successfully used in
cancer therapy. In this study, we performed a compound screen to isolate TRAIL sensitizers and found that one of the identified compounds,
7-benzylidenenaltrexone maleate (BNTX), sensitized
pancreatic cancer cells to TRAIL-induced apoptotic cell death. The combination of BNTX with TRAIL promoted the release of
cytochrome c from mitochondria into cytosol with
caspase activation and a resulting increase in
annexin V-stained cells. From a mechanistic perspective, we found that BNTX downregulated
X-linked inhibitor of apoptosis protein (XIAP) expression when used in combination with TRAIL, and found that TRAIL-induced apoptosis was augmented by
siRNA-mediated knockdown of XIAP. We further demonstrated that BNTX promoted the
ubiquitin/
proteasome-dependent degradation of
XIAP protein via
protein kinase C (PKC) alpha/AKT pathway inhibition. Moreover, combined treatment by BNTX with TRAIL suppressed growth of pancreatic
tumor xenograft of animal model. Therefore, we suggest that
inhibitor of apoptosis protein-mediated resistance of
pancreatic cancer cells to anticancer
therapeutics can be overcome by inhibiting the PKCĪ±/AKT pathway.