Abstract
Several components isolated from Glycyrrhizae radix rhizome (GR), including glycyrrhizin, liquiritin, and liquiritigenin, have been shown to induce cancer cell death and inhibit cancer metastasis. Isoliquiritin apioside (ISLA), a component isolated from GR, has been effective for treating tetanic contraction and genotoxicity. However, the effects of ISLA on the metastasis and angiogenesis of malignant cancer cells and endothelial cells (ECs) have not been reported. In this study, we found that up to 100 μM ISLA did not affect cell proliferation but efficiently suppressed the metastatic ability of HT1080 cells, as assessed by scratch-wound migration, Transwell® migration, scratch-wound invasion, Transwell® invasion, and three-dimensional spheroid invasion. ISLA significantly decreased phorbol 12-myristate 13-acetate (PMA)-induced increases in matrix metalloproteinase (MMP) activities and suppressed PMA-induced activation of mitogen-activated protein kinase as well as NF-κB, which are involved in cancer metastasis. In addition, ILSA treatment reduced the production of pro-angiogenic factors in HT1080 cells, including MMP-9, placental growth factor, and vascular endothelial growth factor under normoxia as well as hypoxia conditions, by impairing the hypoxia-inducible factor-1α pathway. We also found that the abilities of human umbilical vein ECs to migrate across the Transwell® and to form tube-like structures were significantly reduced by ISLA treatment. Moreover, using the chorioallantoic membrane assay, vessel formation with or without vascular endothelial growth factor was significantly suppressed by ISLA. These results suggested that ISLA possesses anti-metastatic and anti-angiogenic abilities in malignant cancer cells and ECs, with no cytotoxicity. ISLA may therefore be a safe and effective lead compound to develop anti-cancer drug for limiting the spread of primary tumors to distant organs to form secondary tumors.
Highlights
Cancer metastasis, the dissemination of cancer cells from the location where they initially formed to anatomically distant parts of the body, is a hallmark of malignant tumors and a major cause of the high mortality of cancer patients (Leber and Efferth, 2009; Valastyan and Weinberg, 2011)
Because it is known that matrix metalloproteinase (MMP) play a major role in promoting metastasis of cancer cells (Deryugina and Quigley, 2006; Halbersztadt et al, 2006; Alaseem et al, 2017), we first examined the proteolytic activity and expression level of MMP-2 and MMP-9 in Isoliquiritin apioside (ISLA)-treated and untreated HT1080 Conditioned Medium (CM)
We found that phorbol 12-myristate 13-acetate (PMA) stimulation remarkably increased MMP-9 activity, whereas ISLA
Summary
The dissemination of cancer cells from the location where they initially formed to anatomically distant parts of the body, is a hallmark of malignant tumors and a major cause of the high mortality of cancer patients (Leber and Efferth, 2009; Valastyan and Weinberg, 2011). Metastasis involves multiple highly coordinated steps, including loss of adhesions between cells and between cells and the extracellular matrix (ECM), invasion into the surrounding ECM, Anti-cancer Activities of Isoliquiritin Apioside intravasation into the lumina of blood vessels, migration and extravasation to distant organs, and colonization of metastatic foci at a secondary site (Patel et al, 2011; Alizadeh et al, 2014). Pro-angiogenic molecules secreted by tumor cells under hypoxic conditions, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and MMPs, can activate their receptors on the surface of ECs and trigger angiogenesis (Harris, 2002; Pugh and Ratcliffe, 2003; Vaupel, 2004). Suppression of metastasis and angiogenesis in tumors by targeting these factors and their upstream pathways is considered to be a promising strategy for the control of malignant tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
