chrysin and daidzin

Colorectal cancer is one of the primary causes of cancer-related mortality worldwide. The tumor microenvironment contains growth factors; inflammatory chemokines, matrix metalloproteinases, and pro-oxidants leading to cancer development and progression. Phytochemicals have been used as the main source of anti-cancer agents. Accordingly, the effect of two natural flavonoids (Chrysin and Daidzein) was investigated on the level of amphiregulin (AREG), chemokine ligand (CXCL1), and matrix metalloproteinase-9 (MMP-9) in 1, 2-dimethylhydrazine dihydrochloride (DMH) induced colorectal cancer. Rats were injected by DMH (40 mg/kg/week S.C.) for 16 weeks concomitantly with 2% dextran sodium sulfate (DSS) in drinking water for three cycles. Rats were orally treated with chrysin (125 and 250 mg/kg) and daidzein (5 and10 mg/kg) three times/week for the last 8 weeks. DMH + DSS group showed a significant (P < 0.05) increase in the levels of AREG (2386 ± 18 vs 1377 ± 10 pg/ml), CXCL1 (18 ± 0.9 vs 6 ± 0.83 g/ml), MMP-9 (1355 ± 88 vs 452 ± 7 pg/ml) compared to normal rats. These findings were associated with a potent antioxidant activity against cytochrome P450 2E1; (CYP2E1). Histopathological findings of the DMH + DSS group showed focal hyperplasia of the mucosa lining overlying crypts with moderate inflammation, dysplastic epithelial cells, and loss of goblet cells. Chrysin and daidzein treatment significantly (P < 0.05) restored the biochemical alterations and reverted histopathological findings near to the normal status. Moreover, chrysin and daidzein exerted anticancer activity against SW620 cells that were associated with decreased the protein expression of p-ERK/ERK and p-AKT/AKT. In conclusion, this study highlighted the potential anticancer role of chrysin and daidzein in the treatment of colon cancer.

Topics: 1,2-Dimethylhydrazine; Amphiregulin; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemokine CXCL1; Colon; Colorectal Neoplasms; Cytochrome P-450 CYP2E1; Dextran Sulfate; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Humans; Isoflavones; Male; Matrix Metalloproteinase 9; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

Recent studies showed that daidzin suppresses ethanol intake in ethanol-preferring laboratory animals. In vitro, it potently and selectively inhibits the mitochondrial aldehyde dehydrogenase (ALDH-2). Further, it inhibits the conversion of monoamines such as serotonin (5-HT) and dopamine (DA) into their respective acid metabolites, 5-hydroxyindole-3-acetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in isolated hamster or rat liver mitochondria. Studies on the suppression of ethanol intake and inhibition of 5-HIAA (or DOPAC) formation by six structural analogues of daidzin suggested a potential link between these two activities. This, together with the finding that daidzin does not affect the rates of mitochondria-catalyzed oxidative deamination of these monoamines, raised the possibility that the ethanol intake-suppressive (antidipsotropic) action of daidzin is not mediated by the monoamines but rather by their reactive biogenic aldehyde intermediates such as 5-hydroxyindole-3-acetaldehyde (5-HIAL) and/or 3,4-dihydroxyphenylacetaldehyde (DOPAL) which accumulate in the presence of daidzin. To further evaluate this possibility, we synthesized more structural analogues of daidzin and tested and compared their antidipsotropic activities in Syrian golden hamsters with their effects on monoamine metabolism in isolated hamster liver mitochondria using 5-HT as the substrate. Effects of daidzin and its structural analogues on the activities of monoamine oxidase (MAO) and ALDH-2, the key enzymes involved in 5-HT metabolism in the mitochondria, were also examined. Results from these studies reveal a positive correlation between the antidipsotropic activities of these analogues and their abilities to increase 5-HIAL accumulation during 5-HT metabolism in isolated hamster liver mitochondria. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also potently inhibit MAO exhibit little, if any, antidipsotropic activity. These results, although inconclusive, are consistent with the hypothesis that daidzin may act via the mitochondrial MAO/ALDH pathway and that a biogenic aldehyde such as 5-HIAL may be important in mediating its antidipsotropic action.

Topics: Alcohol Deterrents; Alcohol Drinking; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Animals; Biological Availability; Cricetinae; Hydroxyindoleacetic Acid; In Vitro Techniques; Isoflavones; Mesocricetus; Mitochondria, Liver; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Serotonin; Structure-Activity Relationship