In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent.
ABSTRACT Polymethoxylated flavonoids are present in citrus fruit in a range of chemical structures and abundance. These compounds have potential for anticarcinogenesis, antitumor, and cardiovascular protective activity, but the effect on angiogenesis has not been well studied.
Human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish (Danio rerio) in vivo models were used to screen and identify the antiangiogenesis activity of seven polymethoxylated flavonoids; namely, hesperetin, naringin, neohesperidin, nobiletin, scutellarein, scutellarein tetramethylether, and sinensetin. Five, excluding naringin and neohesperidin, showed different degrees of potency of antiangiogenesis activity. Sinensetin, which had the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish.
The in vivo structure-activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3' position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity.
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ABSTRACT: Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiological evidence suggests they could play a role in risk reduction in dementia. Amyloid precursor protein (APP) processing and the subsequent generation of Aβ are central to the pathogenesis of Alzheimer’s Disease (AD), as soluble, oligomeric Aβ is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at βγ-mediated APP processing, which lead to identification of a number of flavonoids bioactive at 100nM. Due to known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-) epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Aβ pathology and Aβ levels following short term, 21 day oral delivery of (-) epicatechin in 7 month old TASTPM mice. Further in vitro mechanistic studies suggest this is likely due to indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-) epicatechin may be a potential prophylactic for AD.Neurobiology of Aging 07/2014; · 4.85 Impact Factor
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ABSTRACT: Angiogenesis plays an essential role in many physiological and pathological processes. Auranofin (Ridaura(®)), an important gold (I) complex, is used to treat rheumatoid arthritis. However, the effect of auranofin on blood vessel formation is still unclear. In this study, we investigated the anti-angiogenic activity of auranofin on human umbilical vein endothelial cells (HUVEC) in vitro and zebrafish in vivo. Our results showed that auranofin could inhibit the proliferation, migration and tube formation of HUVECs and disrupted the formation of intersegmental vessels and the subintestinal vessels of zebrafish embryos. Auranofin inhibited the phosphorylation of vascular endothelial growth factor 2 (p-VEGFR2) on HUVECs and suppressed the vascular endothelial growth factor (VEGF) signaling pathway (vegfa, flt-1, kdr and kdrl) but not thioredoxin reductase (TrxR) on zebrafish. Our study suggested that auranofin might serve as a potential anti-angiogenic compound candidate.European journal of pharmacology. 07/2014;
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ABSTRACT: Citrus is a kind of common fruit and contains multiple beneficial nutrients for human beings. Flavonoids, as a class of plant secondary metabolites, exist in citrus fruits abundantly. Due to their broad range of pharmacological properties, citrus flavonoids have gained increased attention. Accumulative in vitro and in vivo studies indicate protective effects of polymethoxyflavones (PMFs) against the occurrence of cancer. PMFs inhibit carcinogenesis by mechanisms like blocking the metastasis cascade, inhibition of cancer cell mobility in circulatory systems, proapoptosis, and antiangiogenesis. This review systematically summarized anticarcinogenic effect of citrus flavonoids in cancer therapy, together with the underlying important molecular mechanisms, in purpose of further exploring more effective use of citrus peel flavonoids.BioMed Research International 01/2014; 2014:453972. · 2.71 Impact Factor