esculetin and Body-Weight

Targeting tumor metabolism by natural products is a novel approach and provides rationale for anti-cancer drug discovery. The present study aims to explore the impact of morin and/or esculetin on c-myc induced energy metabolism in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. In order to achieve this aim we analyzed the expression of glucose and glutamine transporters and the key enzymes of glycolytic pathway besides the markers of neoplastic changes viz., mucin depleted foci (MDF), beta catenin accumulated crypts (BCAC), and markers of cell proliferation viz., proliferating cell nuclear antigen (PCNA), argyrophilic nucleolar antigen (AgNOR), c-myc, c-jun and c-fos. All the parameters tested in the present study are highly influenced by the phytochemicals morin and/or esculetin in a way to prevent colon carcinogenesis. Morin and/or esculetin supplementation effectively targets tumor metabolism via β-cateinin/c-myc signaling and affects glycolysis and glutaminolysis to abrogate colon cancer in rats. The anti-cancer effect of morin is more pronounced than esculetin. The effect obtained through the combined treatment of morin and esculetin is comparable to that of individual supplementation of morin and there is no synergistic effect. Overall individual supplementation of morin scores well as a potential anticancer agent targeting glycolysis and glutaminolysis in colon cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; beta Catenin; Body Weight; Carcinogenesis; Cell Proliferation; Colon; Colonic Neoplasms; Energy Metabolism; Flavonoids; Glycolysis; Male; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Signal Transduction; Survival Rate; Tumor Burden; Umbelliferones

This study investigated the effects and mechanism of esculetin (6,7-dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non-diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Plpp2) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfα and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA

Topics: Animals; Blood Glucose; Body Weight; Chemokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Gene Expression Regulation; Inflammation; Insulin; Lipid Metabolism; Lipid Peroxidation; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Superoxide Dismutase; Umbelliferones

Tumor growth and metastasis are closely associated with the M2 macrophage activation of tumor-associated macrophages (TAMs) in the tumor microenvironment as well as the development of tumor cells. In this study, we examined the antiproliferative, antitumor, and antimetastatic effects of three dihydroxycoumarins (esculetin, fraxetin, and daphnetin) against osteosarcoma LM8 cells (in vitro) and a highly metastatic model in LM8-bearing mice (in vivo). Esculetin (20-100μM) inhibited the proliferation of LM8 cells, whereas fraxetin and daphnetin had no effect. Esculetin inhibited the expressions of cyclin D1, cyclin-dependent kinase (CDK) 4 and matrix metalloproteinase (MMP)-2, and production of both transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) in LM8 cells. Esculetin (3 or 10mg/kg) and fraxetin (10mg/kg) inhibited tumor growth and metastasis to the lung or liver, whereas daphnetin did not. These results suggested that the antitumor and antimetastatic actions of esculetin may be partly attributed to G1 arrest by the inhibition of cyclin D1 and CDK4 expression, while its antiangiogenic action may have been due to the inhibition of MMP-2 expression and TGF-β1 and VEGF productions at tumor sites. Esculetin (10-100μM) and fraxetin (50-100μM) inhibited the production of interleukin (IL)-10, monocyte chemoattractant protein (MCP)-1, and TGF-β1 during the differentiation of M2 macrophages by reducing the phosphorylation of Stat 3 without affecting its expression. These results also suggested that the antitumor and antimetastatic actions of esculetin or fraxetin may be due to the regulated activation of TAM by M2 macrophage differentiation in the tumor microenvironment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Body Weight; Cell Differentiation; Cell Line, Tumor; Cell Polarity; Cell Proliferation; Chemokine CCL2; Coumarins; Cyclin-Dependent Kinase 4; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Interleukin-10; Macrophage Activation; Macrophages; Male; Matrix Metalloproteinase 2; Mice; Neoplasm Metastasis; Osteosarcoma; STAT3 Transcription Factor; Tetradecanoylphorbol Acetate; Transforming Growth Factor beta1; Umbelliferones; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Effects of esculetin (6,7-dihydroxycoumarin) and its glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, N-nitrosobis(2-oxopropyl)amine (BOP), were examined in the pancreas of female Syrian golden hamsters. Animals were administered esculetin by gastric intubation into the stomach 30 min before BOP administration or ingestion of a diet containing esculin for 7 days before BOP administration, and killed 1 or 4h after BOP treatment, and the contents of thiobarbituric acid-reacting substrates (TBARS) and 8-oxodG in the pancreas were determined. Both compounds suppressed significantly the BOP-induced increases in 8-oxodG and TBARS contents in hamster pancreas. We further investigated the effect of esculin on pancreatic carcinogenesis by the rapid production model induced by augmentation pressure with a choline-deficient diet, ethionine, methionine and BOP. Esculin was given ad libitum as a 0.05% aqueous solution in either the initiation or promotion phases. The incidence of invasive tumors in animals given esculin during the initiation phase was significantly smaller than in the control group, while esculin given during the promotion phase showed no apparent effects. These results suggest that the intake of esculin has an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in hamster pancreas.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animal Feed; Animals; Body Weight; Carcinogens; Cell Nucleus; Choline; Cricetinae; Deoxyguanosine; DNA; Esculin; Ethionine; Female; Methionine; Nitrosamines; Organ Size; Oxidation-Reduction; Pancreas; Thiobarbituric Acid Reactive Substances; Umbelliferones