3-hydroxy-4-3--4--5--tetramethoxychalcone and benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. Here we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIP(L)) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIP(L) and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIP(L) and c-IAPs degradation. Altogether, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIP(L) and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.

Topics: A549 Cells; Amino Acid Chloromethyl Ketones; Apoptosis; Autophagy; Blotting, Western; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 3; Caspase 8; Caspase Inhibitors; Cell Line, Tumor; Cell Survival; Chalcones; Dose-Response Relationship, Drug; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Proteolysis; TNF-Related Apoptosis-Inducing Ligand