Growth Inhibitory Effects of Dipotassium Glycyrrhizinate in Glioblastoma Cell Lines by Targeting MicroRNAs Through the NF-κB Signaling Pathway.

Gabriel Alves Bonafé,Jussara Vaz Ziegler,Marcelo Lima Ribeiro,Kazuo Umezawa,Thalita Rocha,Jéssica Silva Dos Santos,Manoela Marques Ortega

doi:10.3389/fncel.2019.00216

Gabriel Alves Bonafé, Jussara Vaz Ziegler + Show 5 more

Open Access

https://doi.org/10.3389/fncel.2019.00216

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Abstract

It has been shown that nuclear factor kappa-B (NF-κB) is constitutively activated in glioblastoma (GBM), suggesting that the pathway could be a therapeutic target. Glycyrrhetic acid (GA), a compound isolated from licorice (Glycyrrhiza glabra), has been shown to decrease cell viability and increases apoptosis in human cancer cell lines by NF-κB signaling pathway suppression. Dipotassium glycyrrhizinate (DPG), a dipotassium salt of GA, has anti-inflammatory properties without toxicity. The current study examined the effectiveness of DPG as an anti-tumor in U87MG and T98G GBM cell lines. Additionally, we assessed DPG as a candidate for combinational therapy in GBM with temozolomide (TMZ). Our results demonstrated that the viability of U87MG and T98G cells significantly decreased in a time- and dose-dependent manner after DPG treatment, and the apoptotic ratio of DPG-treated groups was significantly higher than that of control groups. In addition, DPG in combination with TMZ revealed synergistic effects. Furthermore, the expression of NF-κB-luciferase-reporter in transfected GBM cell lines was remarkably reduced after DPG exposure by up-regulating miR16 and miR146a, which down-regulate its target genes, IRAK2 and TRAF6. A reduced neuro-sphere formation was also observed after DPG in both GBM cells. In conclusion, DPG presented anti-tumoral effect on GBM cell lines through a decrease on proliferation and an increase on apoptosis. In addition, our data also suggest that DPG anti-tumoral effect is related to NF-κB suppression, where IRAK2- and TRAF6-mediating miR16 and miR146a, respectively, might be a potential therapeutic target of DPG.

Highlights

Glioblastoma (GBM) represents 65% of all adult nervous system cancers, being the most common among astrocytic tumors and characterized with an average survival period of less than 15 months (Krex et al, 2007; Brandes et al, 2008; Johnson and O’Neill, 2012; Shahar et al, 2012)
Our findings suggest that Dipotassium glycyrrhizinate (DPG) treatment can confer inhibitory effects on human GBM cell lines, including inhibiting proliferation and inducing apoptosis, which is possibly related to the NF-κB-mediated pathway through miR16 and miR146a inhibition
The present study examined the effectiveness of DPG as an antitumor in U87MG and T98G GBM cell lines

Summary

Introduction

Glioblastoma (GBM) represents 65% of all adult nervous system cancers, being the most common among astrocytic tumors and characterized with an average survival period of less than 15 months (Krex et al, 2007; Brandes et al, 2008; Johnson and O’Neill, 2012; Shahar et al, 2012). Many dietary supplements and plant-derived compounds have been published as promising anti-tumor products by enhancing apoptosis-related pathways in tumor cells (Cassileth and Deng, 2004; Cragg and Newman, 2005). It has been shown that G is effective against colon, lung, leukemia, melanoma, and GBM cell lines (Abe et al, 1987; Chung et al, 2000; Kobayashi et al, 2002; Cassileth and Deng, 2004; Cragg and Newman, 2005; Menegazzi et al, 2008; Khan et al, 2013; Huang et al, 2014). GA, an aglycone of G, has been demonstrated to have apoptotic effects on human hepatoma, promyelocytic leukemia, stomach cancer, Kaposi sarcoma-associated herpesvirus-infected cells, and prostate cancer cells in vitro by inducing DNA fragmentation and oxidative stress (Hibasami et al, 2005, 2006; Sivasakthivel et al, 2008)

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