The substitution pattern of anthocyanidins affects different cellular signaling cascades regulating cell proliferation.
The aglycons of the most abundant anthocyanins in food, cyanidin (cy) and delphinidin (del), represent potent inhibitors of the epidermal growth factor receptor (EGFR). Structure-activity studies show that the presence of vicinal hydroxy substituents at the phenyl ring at the 2-position (B-ring) is crucial for target interaction. The presence of a single hydroxy group or introduction of methoxy substituents at the B-ring results in a substantial loss of inhibitory properties. However, biological activity is not exclusively limited to compounds bearing vicinal hydroxy groups. A contradictory structure-activity relationship is observed for the inhibition of cAMP-specific phosphodiesterases (PDEs). Of the anthocyanidins tested, malvidin, bearing methoxy substituents in the 3'- and 5'-positions, most effectively inhibited cAMP hydrolysis. The absence of methoxy groups and/or replacement by hydroxy substituents was found to strongly diminish PDE-inhibitory properties. We found that either effective EGFR inhibition or effective PDE inhibition is required to achieve a shut-down of the central mitogen-activated protein kinase (MAPK) pathway, a signaling cascade crucial for the regulation of cell growth. This is consistent with the finding that efficient reduction of cell growth is limited to anthocyanidins that are potent EGFR- or PDE-inhibitors including cy and del or malvidin (mv), respectively. In summary, depending on the substitution pattern at the B-ring, anthocyanidins interfere with different signaling cascades involved in the regulation of cell growth.
Marko
Doris
D
Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Kaiserslautern, Germany. marko@rhrk.uni-kl.de
Puppel
Nicole
N
Tjaden
Zeina
Z
Jakobs
Sandra
S
Pahlke
Gudrun
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000872:Anthocyanins / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D006868:Hydrolysis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms
D000872:Anthocyanins; D004791:Enzyme Inhibitors; C065861:malvidin; D000242:Cyclic AMP; D066246:ErbB Receptors; D015105:3',5'-Cyclic-AMP Phosphodiesterases