Osthole Increases the Sensitivity of Liver Cancer to Sorafenib by Inhibiting Cholesterol Metabolism.

Osthole is a natural product that has an inhibitory effect on liver cancer, but its effect on the sensitivity of liver cancer to sorafenib is poorly understood. Here, we investigated the effect of osthole and possible sensitization mechanisms. Our results showed that the combination of 2.5 µM sorafenib and 10 µM osthole had significantly synergistic inhibitory effects on proliferation, colony formation, and migration of HCCLM3, sorafenib-resistant HCCLM3 (HCCLM3-SR), and SK-Hep-1 cells. After treatment of HCCLM3 cells-inoculated subcutaneous xenotransplanted tumor mice with 100 mg/kg osthole, 70 mg/kg sorafenib or their combination for 24 day, the tumor volume, tumor weight, and tumor weight coefficient were significantly lower in the osthole + sorafenib group than in the sorafenib group. Compared with the control group, the total cholesterol and low density lipoprotein-cholesterol contents in serum and tumor tissue were significantly decreased in the osthole or osthole + sorafenib groups, the sterol regulatory element binding protein (SREBP)-2c, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) protein expressions in tumor tissue were significantly downregulated as well. In conclusion, osthole can increase the sensitivity of liver cancer to sorafenib, and the mechanism is related to the downregulations of SREBP-2c, HMGCR, and LDLR protein expressions and subsequent inhibition of cholesterol metabolism.

Apigenin increases radiosensitivity of glioma stem cells by attenuating HIF-1α-mediated glycolysis.

Apigenin, a natural flavonoid compound present in a variety of edible plants and health foods, has an anti-tumor effect and inhibits hypoxia inducible factor-lα (HIF-1α) expression in hypertrophic cardiac tissues. However, whether or not apigenin has a radiosensitization effect on glioma stem cells (GSCs) is unknown. Our present study aimed to investigate the effect of apigenin and its possible mechanisms. The human GSCs SU3 and its radioresistance line SU3-5R were treated with apigenin, radiation, or their combination, and the cell proliferation, migration, colony formation, and intracellular lactic acid and glycolytic related protein expressions were determined. Additionally, a cell model with hypoxia-induced HIF-1α expression was used and treated with apigenin. The current results displayed that the combination of apigenin and radiation could synergically reduce the viability, colony formation, and migration of the both GSCs. Moreover, this combination could also decrease the radiation-induced increments of glycolytic production lactic acid in the both GSCs and related protein expressions, including HIF-1α, glucose transporter (GLUT)-1/3, nuclear factor kappa B (NF-κB) p65, and pyruvate kinase isozyme type M2 (PKM2). Further study confirmed that after treatment of hypoxia-cultured SU3 or SU3-5R cells with apigenin, the expression levels of HIF-1α, GLUT-1/3, NF-κB p65, and PKM2 proteins were reduced. These results demonstrated that apigenin could increase the radiosensitivity of GSCs and its radiosensitization mechanisms were attributable to the attenuation of glycolysis, which might result from the inhibition of HIF-1α expression and subsequent reductions of GLUT-1/3, NF-κB, and PKM2 expressions.

Chrysanthemum morifolium extract improves hypertension-induced cardiac hypertrophy in rats by reduction of blood pressure and inhibition of myocardial hypoxia inducible factor-1alpha expression.

CONTEXT: Chrysanthemum morifolium Ramat. (Asteraceae) extract (CME) possesses a vasodilator effect in vitro. However, the use of polyphenol-rich CME in the treatment of hypertension-induced cardiac hypertrophy has not been reported. OBJECTIVE: We investigated the effect of polyphenol-rich CME on hypertension-induced cardiac hypertrophy in rats and its possible mechanism of action. MATERIALS AND METHODS: The Sprague-Dawley rat model with cardiac hypertrophy was induced by renovascular hypertension. The blood pressure, cardiac weight index, free fatty acids (FFA) in serum and myocardium, and protein expressions of myocardial hypoxia inducible factor-1α (HIF-1α), peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1a (CPT-1a), pyruvate dehydrogenase kinase-4 (PDK-4) and glucose transporter-4 (GLUT-4) were measured after treating hypertensive rats with polyphenol-rich CME of anthodia 75-150 mg/kg once daily for 4 weeks. A myocardial histological examination was also conducted. RESULTS: After CME treatment, the blood pressure, cardiac weight and cardiac weight index decreased by 5.7-9.6%, 9.2-18.4% and 10.9-20.1%, respectively, and the cardiomyocyte cross-sectional area also decreased by 8.3-30.4%. The CME treatment simultaneously decreased the FFA in serum and myocardium and protein expressions of myocardial HIF-1α and GLUT-4, and increased the protein expressions of myocardial PPARα, CPT-1a and PDK-4, especially in the CME 150 mg/kg group (p < 0.05 or p < 0.01). DISCUSSION AND CONCLUSION: Polyphenol-rich CME may alleviate hypertensive cardiac hypertrophy in rats. Its mechanisms may be related to the reduction of blood pressure and amelioration of the myocardial energy metabolism. The latter may be attributed to the inhibition of HIF-1α expression and subsequent modulation of PPARα-mediated CPT-1a, PDK-4 and GLUT-4 expressions.

Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats.

Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1α expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1α. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1α protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) α, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARγ, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT)-4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF-1α expression and, subsequently increasing the expressions of myocardial PPARα and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARγ and its target genes GPAT and GLUT-4.