In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: Identifying sinensetin as a novel antiangiogenesis agent

Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Taipa, Macao SAR, PR China.
Molecular Nutrition & Food Research (Impact Factor: 4.6). 06/2012; 56(6):945-56. DOI: 10.1002/mnfr.201100680
Source: PubMed


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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Available from: Ailin Liu, Jun 11, 2015
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    • "With human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish in vivo models, PMFs showed different degrees of potency of antiangiogenesis activity. Sinensetin, which showed 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 [54]. Nobiletin differs from sinensetin by having methylation at the C8 position. "
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    • "One of major limitations of commonly used in vitro assays which can precisely reflect the pharmacodynamic change of a specific mode of action to a specific cell type and/or molecular target, is that these assays do not facilitate the assessment of absorption, distribution, metabolism, and excretion (ADME) [23]. Recently, zebrafish (Danio rerio) has become an ideal environmentally friendly and economical in vivo drug screening model for improving various drug-like properties such as pharmacodynamic, absorption and metabolism simultaneously [24]. "
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