The hdac1 inhibitor cbud-1001 enhances trail-induced apoptosis in colorectal cancer cells

Background/Aim: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-tumor agent.However, resistance to TRAIL has been reported in a number of clinical trials.In this study, we investigated the molecular mechanisms by which a novel histone deacetylase (HDAC) inhibitor, CBUD-1001, sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis.Materials and Methods: Apoptotic cell death induced by CBUD-1001 and/or TRAIL was assessed on human CRC cells using the MTT assay, FACS analysis and nuclei staining.The involved molecular mechanisms were explored through western blotting analysis.Results: We demonstrated that combined with CBUD-1001, TRAIL significantly enhanced TRAIL-induced apoptosis in CRC cells via mitochondria-mediated pathways.We also found that hyper-acetylation of histone by CBUD-1001 treatment leads to up-regulation of death receptor (DR) 5 in a dose- A nd timedependent manner.Furthermore, we identified that enhanced sensitivity to TRAIL by combination with CBUD-1001 depends on the MAPK/CHOP axis, being a key mediator of DR5.Conclusion: A novel HDAC inhibitor CBUD-1001 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and that CBUD-1001 and TRAIL combination treatment offers an effective strategy to overcome TRAIL resistance in CRC cells.