The aglycons of the most abundant anthocyanins in food, cyanidin (cy) and delphinidin (del), were found to inhibit the growth of human tumor cells in vitro in the micromolar range, whereas malvidin (mv), a typical anthocyanidin in grapes, was less active. The aglycons preferentially inhibited the growth of the human vulva carcinoma cell line A431, overexpressing the epidermal growth-factor receptor (EGFR). The glycosides cyanidin-3-beta-D-galactoside (cy-3-gal, idaein) and malvidin-3-beta-D-glucoside (mv-3-glc, oenin) did not affect tumor cell growth up to 100 microM. The tyrosine kinase activity of the EGFR, isolated from A431 cells, was potently inhibited by cy and del. Mv and the glycosides cy-3-gal and mv-3-glc were inactive up to 100 microM. In intact cells the influence of anthocyanin treatment on downstream signaling cascades was investigated by measuring the phosphorylation of the transcription factor Elk-1. A431 cells were transiently transfected with a luciferase reporter gene construct whose expression is controlled by MAP kinase pathway dependent phosphorylation of a GAL4-Elk-1 fusion protein. We found that cy and del inhibited the activation of the GAL4-Elk-1 fusion protein in the concentration range where growth inhibition was observed. Thus, the anthocyanidins cy and del are potent inhibitors of the EGFR, shutting off downstream signaling cascades. These effects might contribute substantially to the growth-inhibitory properties of these natural food constituents.

We investigated the effect of a series of Maillard reaction products formed from carbohydrates under household heating conditions on the growth of human tumor cells in vitro. 4-Hydroxy-5-methyl-3-(2H)-furanone (1) was found to potently enhance the proliferation of human tumor cells. In contrast, the Maillard-type chromophores 2-(2-furyl)methylidene-4-hydroxy-5-methyl-2H-furan-3-one (2), 4-(2-furyl)-7-[(2-furyl)methylidene]-2-hydroxy-2H,7H,8aH-pyrano[2,3-b]- pyran-3-one (6), and 3-hydroxy-4[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2 dione (13) inhibited the growth of human tumor cells in vitro in the low micromolar range. GXF251L cells (gastric carcinoma), synchronized by serum deprivation, were retained in the G1-phase of the cell cycle after treatment with 2, 6, or 13 for 24 h. Concomitantly, a distinct sub-G1 peak was observed, indicative for apoptosis induction. DNA fragmentation was further investigated by ELISA using antibodies raised against histones and DNA. 2 induced a significant increase of fragmented DNA at concentrations > or = 30 microM. After treatment with compound 6, DNA fragmentation was observed at a higher concentration range (> or = 50 microM), whereas incubation with 13 resulted in a marked DNA fragmentation already at 20 microM. On the protein level, the activation of caspase 3, as an early marker for apoptosis induction, was determined. The results were almost identical to those obtained in the DNA fragmentation ELISA. In summary, Maillard reaction products potently modulating the growth of human tumor cells were identified. The Maillard-type chromophores 2, 6, and 13 were found to interfere with the proliferation of gastric carcinoma cells, causing cell cycle arrest and apoptosis induction.

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