Structural Insight into the In Vitro Anti-Intravasative Properties of Flavonoids

Julia Eichsteininger,Georg Krupitza,Walter Jäger,Kerstin Kirisits,Claudia Smöch,Liselotte Krenn,Christa Stadlbauer,Chi Huu Nguyen,Ali Özmen,Gerhard Ecker

doi:10.3390/scipharm87030023

Julia Eichsteininger, Georg Krupitza + Show 8 more

Open Access

https://doi.org/10.3390/scipharm87030023

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Abstract

We investigated the effect of 21 flavonoids in a three-dimensional in vitro system for their ability to inhibit gap formation by MCF-7 breast cancer spheroids in monolayers of lymphendothelial cells. Different representatives of the classes of flavones, flavonols, and flavanones were tested in the circular chemorepellent-induced defects (CCID)-assay. Bay11-7082, a known inhibitor of CCID formation served as the positive control. This study provides the first comparison of the potential of flavonoids to suppress features influencing the intravasation of MCF-7 breast cancer cells aggregates through the lymph endothelial barrier. The most significant effects were seen after incubation with the flavones luteolin, chrysin, and apigenin. Additional hydroxylation or methoxylation in positions 6 or 8, as expected, resulted in decreased activity. The tested flavanones remained without or low efficacy.

Highlights

Intravasation through the lymphatic border is an early- and rate-limiting step in the metastatic cascade of breast cancer [1,2,3]
Human microvessel endothelial cells were purchased from Clonetics (Basel, Switzerland), immortalized with human telomerase cDNA (TERT1) [17], and subsequently lymph endothelial cell population was isolated by single cell cloning [18]
circular chemorepellent-induced defects (CCID) areas were calculated with the Axiovision Re. 4.5 software (Carl Zeiss)

Summary

Introduction

Intravasation through the lymphatic border is an early- and rate-limiting step in the metastatic cascade of breast cancer [1,2,3]. As from 1981 to 2014 approximately 83% of the approved small molecule anticancer drugs were natural products, based on natural compounds or mimicking them in different ways [4]. We tested traditional medicinal plants regarding their anti-intravasative properties [5,6,7,8]. In a study on the effects of different Scrophularia extracts on breast cancer cellsproliferation, cell death, and intravasation through lymph endothelial cell barriers, a methanolic extract of Scrophularia lucida L. (Scrophulariaceae) proved active in inhibiting intravasation in vitro [8]. An activity-guided fractionation of this extract revealed hispidulin, a member of the class of flavonoids, as significantly contributing to this activity [9]

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