Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release

Delphine Lamoral-Theys, Nathalie Wauthoz, Petra Heffeter, Véronique Mathieu, Utte Jungwirth, Florence Lefranc, Jean Nève, Jacques Dubois, François Dufrasne, Karim Amighi, Walter Berger, Philippe Gailly, Robert Kiss

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12 Citations (Scopus)

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 IC50in 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.

Original languageEnglish
Pages (from-to)1421-1434
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • Actin cytoskeleton
  • Cancer
  • Kinases
  • Lung
  • Polyphenols

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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