Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

Abstract

Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.

RNA interference-mediated targeting of urokinase plasminogen activator receptor and matrix metalloproteinase-9 gene expression in the IOMM-lee malignant meningioma cell line inhibits tumor growth, tumor cell invasion and angiogenesis

“…Our study revealed that RNAi-mediated downregulation of uPAR and MMP-9 resulted in a decrease in the migration of IOMM-Lee tumor spheroids cultured on a vitronectin-coated substrate. Our results are in agreement with earlier studies that reported the involvement of the uPAuPAR plasminolytic system in tumor migration in glioblastoma cells (54).…”

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

“…Indeed delphinidin was shown to be a potent inhibitor of glioblastoma cell migration. This effect is though to be mediated through a decrease in the expression of both urokinase-type plasminogen activator receptor and the low-density lipoprotein receptor-related protein, at the transcriptional levels (Lamy et al, 2007). Moreover, there is evidence that induction of apoptosis by anthocyanidins is a pivotal mechanism of their cancer chemopreventive functions (Yeh and Yen, 2005).…”

Inhibitors of Autoactivation of Plasma Hyaluronan-Binding Protein (Factor VII Activating Protease)

“…For example, compound 1 inhibits proteasomal chymotrypsin-like activity (IC 50 ϭ0.035 mM), 23) collagenase (effective at 7-37 mM), 24) aldose reductase (IC 50 ϭ0.070 mM), 25) and epidermal growth factor (EGF) receptor tyrosine kinase (IC 50 ϭ0.3 mM), 26) and induces tumor cell death (effective at 10-30 mM). 27,28) Compound 2 inhibits u-PA-catalyzed plasminogen activation (IC 50 ϭ5 mM) 29) and EGF receptor tyrosine kinase (IC 50 ϭ0.1 mM), 30) and induces tumor cell death (effective at 30-300 mM). 31,32) Compound 3 inhibits neutrophil elastase (IC 50 ϭ150 mM), 33) human immunodeficiency virus (HIV) integrase (IC 50 ϭ0.7 mM), 34) and aldose reductase (IC 50 ca.…”

“…1). None of the hit compounds were inhibitory to heparin-induced autoactivation and the active form of PHBP at a concentration of 10 mg/ml, which corresponded to 17,19,20,38,30,35,35,18,29, and 26 mM for compounds 4-13, respectively (data not shown). The gallic acid derivatives, flavonoids, and caffeic acid derivatives were subjected to further characterizations as described below.…”

“…3D). The activity of (Ϫ)-epigallocatechin gallate (29), which has an additional hydroxyl group at position 5Ј in the B-ring of 28, was ca. 1/5 the activity of 28 (IC 50 ϭ1.3Ϯ0.1 mM).…”