Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca(2+) release.

Lamoral-Theys, Delphine;Wauthoz, Nathalie;Heffeter, Petra;Mathieu, Véronique;Dufrasne, François E.;et.al.
(2012) Journal of Cellular and Molecular Medicine (Print) : a journal of translational medicine — Vol. 16, n° 7, p. 1421-1434 (2012)

Files

Lamoral-TheysKiss2012.pdf
  • Open Access
  • Adobe PDF
  • 993.87 KB
Download

Details

Authors
  • Lamoral-Theys, DelphineULB
    Author
  • Wauthoz, NathalieULB
    Author
  • Heffeter, PetraMedical University Vienna
    Author
  • Mathieu, VéroniqueULB
    Author
  • Gailly, PhilippeUCLouvain
    Author
  • Dufrasne, François E.UCLouvain
    Author
Show more
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.
Affiliations

Citations

  • APA
  • Chicago
  • FWB

Lamoral-Theys, D., Wauthoz, N., Heffeter, P., Mathieu, V., Jungwirth, U., Lefranc, F., Nève, J., Dubois, J., Amighi, K., Berger, W., Gailly, P., Kiss, R., & Dufrasne, F. E. (2012). Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca(2+) release. Journal of Cellular and Molecular Medicine (Print) : a journal of translational medicine, 16(7), 1421-1434. https://doi.org/10.1111/j.1582-4934.2011.01403.x (Original work published 2012)