title: Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release.
abstract: Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs.
authors.affiliation: Laboratoire de Chimie BioAnalytique, Toxicologie et Chimie Physique Appliquée, Brussels, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Lamoral-Theys
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wauthoz
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: Utte
authors.initials: U
authors.lastname: Jungwirth
authors.forename: Florence
authors.initials: F
authors.lastname: Lefranc
authors.forename: Jean
authors.initials: J
authors.lastname: Nève
authors.forename: Jacques
authors.initials: J
authors.lastname: Dubois
authors.forename: François
authors.initials: F
authors.lastname: Dufrasne
authors.forename: Karim
authors.initials: K
authors.lastname: Amighi
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D054697:Cytostatic Agents / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008938:Mitosis; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059808:Polyphenols / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D059808:Polyphenols; D010770:Phosphotransferases; D003474:Curcumin; D002118:Calcium