Background: Stilbenes, 1,2-diphenylethen derivatives, including resveratrol and combretastatins,
show anticancer features especially against tumor angiogenesis. Fosbretabulin, CA-4, in
combination with carboplatin, is in the last stages of clinical tests as an inhibitor of thyroid cancer.
The mode of action of these compounds involves suppression of angiogenesis through interfering
with tubulin (de)polymerization.
Objective: We have previously synthesized five E-2-hydroxystilbenes and seven dibenzo
[b,f]oxepins in Z configuration, with methyl or nitro groups at varied positions. The aim of the present
work was to evaluate the anticancer activity and molecular mechanism(s) of action of these
Results: Two healthy, EUFA30 and HEK293, and two cancerous, HeLa and U87, cell lines were
treated with four newly synthetized stilbenes and seven oxepins. Two of these compounds, JJR5 and
JJR6, showed the strongest cytotoxic effect against cancerous cells tested and these two were selected
for further investigations. They induced apoptosis with sub-G1 or S cell cycle arrest and
PARP cleavage, with no visible activation of caspases 3 and 7. Proteomic differential analysis of
stilbene-treated cells led to the identification of proteins involved almost exclusively in cell cycle
management, apoptosis, DNA repair and stress response, e.g. oxidative stress.
Conclusion: Among the newly synthesized stilbene derivatives, we selected two as potent anticancer
compounds triggering late apoptosis/necrosis in cancerous cells through sub-G1 phase cell cycle
arrest. They changed cyclin expression, induced DNA repair mechanisms, enzymes involved in
apoptosis and oxidative stress response. Compounds JJR5 and JJR6 can be a base for structure
modification(s) to obtain even more active derivatives.