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.