Evaluation of Anti-cancer Activity of Stilbene and Methoxydibenzo[b,f]oxepin Derivatives

D. Garbicz , D. Mielecki , M. Wrzesiński , T. Pilżys , M. Marcinkowski , J. Piwowarski , J. Dębski , E. Palak , Przemysław Szczeciński , Hanna Krawczyk , E. Grzesiuk

Abstract

Background: Stilbenes,1,2-diphenylethen derivatives, including resveratrol and combre-tastatins, showanticancer featuresespeciallyagainst tumor angiogenesis. Fosbretabulin, CA-4, in combination with carboplatin,isin the laststagesof clinicaltests asaninhibitor of thyroid cancer. Themode of action of these compoundsinvolves suppression of angiogenesis through interfering with tubulin (de)polymerization. Objective: Wehavepreviously synthesized five E-2-hydroxystilbenes and seven dibenzo [b,f]oxepinsin Zconfiguration,with methylornitro groups atvaried positions.The aimofthepre-sentworkwasto evaluatethe anticancer activity andmolecular mechanism(s)ofactionofthese compounds. Results: Twohealthy,EUFA30 and HEK293, and twocancerous,HeLa and U87, celllineswere treatedwith fournewlysynthetized stilbenes and sevenoxepins.Two of these compounds, JJR5and JJR6, showed the strongest cytotoxic effectagainstcancerous cells tested and these twowere se-lectedfor furtherinvestigations.Theyinduced apoptosiswith sub-G1 orS cellcyclearrest and PARP cleavage,withno visible activationof caspases3and7.Proteomic differential analysisof stilbene-treatedcells led tothe identification ofproteins involvedalmost exclusively in cellcycle management,apoptosis, DNA repairand stressresponse, e.g.oxidative stress. Conclusion: Among the newlysynthesized stilbene derivatives,we selectedtwo aspotent antican-cer compoundstriggering lateapoptosis/necrosisin cancerous cells through sub-G1phasecell cycle arrest.They changed cyclinexpression,induced DNA repairmechanisms,enzymes involved in apoptosisand oxidativestress response.CompoundsJJR5 and JJR6 can be abaseforstructure modification(s)toobtain evenmore active derivatives