4＇-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death

Aim： To examine the antitumor effect of 4＇-chloro-3,5-dihydroxystilbene, a resveratrol derivative, on lung adenocarcinoma A549 cells. Methods： The cytotoxic IC50 was determined by direct cell counting. Flow cytometry, monodansylcadaverine （MDC） staining, transfection, Western blot and a proteasome activity assay were used to study the cellular mechanism of 4＇-chloro-3,5-dihydroxystilbene. A xenograft nude mouse model was used to analyze the antitumor effect in vivo. Results： 4＇-Chloro-3,5-dihydroxystilbene induced a rapid and persistent increase in the intracellular reactive oxygen species in the cells, but the cell death could not be inhibited by two antioxidant agents. The derivative caused sub-G1 formation, a decrease in the mitochondria membrane potential and poly （ADP-ribose） polymerase degradation, and the caspase inhibitor Z-VAD-FMK could partially prevent cell death. It also induced a significant increase in intracellular acidic vacuoles, LC3-11 formation and intracellular GFP-LC3 aggregation. An autophagic inhibitor partially reversed cell death. Additionally, 4＇-chloro-3,5-dihydroxystilbene induced the accumulation of ubiquitinated conjugates and inhibited proteasome activity in cells. In an in vivo study, 4＇-chloro-3,5-dihydroxystilbene retarded tumor growth in nude mice. Conclusion： These data suggest that the resveratrol derivative 4＇-chloro-3,5-dihydroxystilbene could be developed as an anti-tumor compound.