Butein sensitizes human leukemia cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL)

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is frequently encountered, requiring combined treatments with sensitizing agents. It is, therefore, important to find nontoxic drugs which can be used together with TRAIL. In this study, we investigated natural compounds that can overcome resistance to TRAIL, and found that butein, a polyphenol, exhibits significant synergism with TRAIL. Treatment with TRAIL in combination with subtoxic concentrations of butein sensitizes TRAIL-resistant human leukemia U937 cells to apoptosis. Butein increased caspase-3 activity and expression of death receptor DR5. The apoptotic cell death induced by combined treatment was significantly reduced by z-DEVD-fmk, a caspase-3 inhibitor, suggesting a critical role of caspase-3 in apoptosis. These results indicate that butein sensitizes TRAIL-resistant U937 cells to TRAIL-induced apoptosis in a caspase-3 dependent manner which might be correlated with upregulation of death receptor DR5. Our data suggests that combined treatment with butein and TRAIL may provide a safe and effective strategy for treating cancer.