Abstract
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-II 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.
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Acknowledgements
This work was supported by grants from the National Science Council of Taiwan (NSC97-2320-B-415-002) and the Buddhist Tzuchi Dalin General Hospital (DTCRD97(2)-08).
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The structure and cytotoxicity of resveratrol derivaties. (JPG 67 kb)
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Wu, Jy., Tsai, Kw., Shee, Jj. et al. 4′-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death. Acta Pharmacol Sin 31, 81–92 (2010). https://doi.org/10.1038/aps.2009.182
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DOI: https://doi.org/10.1038/aps.2009.182
