Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma

Abstract

Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, the most abundant flavonoid, has been shown to have anti-ulcer, anti-cancer, antioxidant, and anti-inflammatory properties. Latent Epstein-Barr virus (EBV) infection can lead to serious malignancies, such as, Burkitt's lymphoma, Hodgkin's disease and gastric carcinoma(GC), and (Epstein-Barr virus associated gastric carcinoma) EBVaGC is one of the most common EBV-associated cancers. In this study, the authors first examined the anti-cancer effects of quercetin and isoliquiritigenin in vivo xenograft animal models implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(−) human gastric carcinoma (MKN74), and then explored the molecular mechanisms responsible for their anti-cancer activities. The results obtained showed that anti-cancer effect of quercetin was greater than isoliquiritigenin in mice injected with EBV(+) human gastric carcinoma (SNU719) cells. On the other hand, quercetin and isoliquiritigenin had similar anti-cancer effects in mice injected with EBV(−) human gastric carcinoma (MKN74) cells. Interestingly, quercetin inhibited EBV viral protein expressions, including EBNA-1 and LMP-2 proteins in tumor tissues from mice injected with EBV(+) human gastric carcinoma. Quercetin more effectively induced p53-dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this induction was correlated with increased expressions of the cleaved forms of caspase-3, -9, and Parp. In EBV(−)human gastric carcinoma (MKN74), both quercetin and isoliquiritigenin induced the expressions of p53, Bax, and Puma and the cleaved forms of caspase-3 and -9 and Parp at similar levels.

Anticancer potential of quercetin: A comprehensive review

“…In human pancreatic cancer cell lines CFPAC‐1 and SNU‐213, quercetin‐3‐O‐glucoside suppresses the migratory activity induced by transforming growth factor‐beta (TGF‐β) and vascular endothelial growth factor A even at relatively low dosages in CFPAC‐1, but not in bFGF‐activated SNU‐213 cells. In addition, co‐treatment with low dose of gemcitabine and quercetin‐3‐O‐glucoside exhibited synergistic inhibition effects on the infiltrate activity induced by bFGF in CFPAC‐1 and SNU‐213 cells (J. Lee, Lee, Kim, & Kim, ; H. H. Lee, Lee, Shin, et al, ).…”

“…Quercetin viably prompted p53‐dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this enlistment was related with expanded expressions of the separated types of caspase‐3, ‐9, and Parp. In EBV(−) human gastric carcinoma (MKN74), quercetin instigated the expressions of p53, Bax, and Puma and the separated types of caspase‐3 and ‐9 and Parp at comparative levels (J. Lee, Lee, Kim, et al, ; H. H. Lee, Lee, Shin, et al, ). In gastric cancer stem cells, quercetin induced cell apoptosis in a mitochondrial‐dependent approach through (a) lessening in mitochondrial membrane potential, (b) enhancement of caspase‐3 and ‐9, (c) down‐regulation of Bcl‐2, and (d) up‐regulation of Bax and cytochrome c. It, likewise, caused mitochondrial apoptotic‐dependent growth inhibition by diminishing the PI3K‐Akt signaling and suppressed the overexpression of Bcl‐2 and kept the reduction in mitochondrial film potential.…”

Liquiritin represses proliferation , migration and invasion of colorectal cancer cells through inhibition of the miR-671/HOXB3 signaling pathway

“…Liquiritin is one of active ingredients extracted from the root of Glycyrrhiza uralensis. Emerging studies have shown that liquiritin has multiple beneficial effects, such as anti-oxidation, anti-allergy, immunity-enhancing, anti-thrombosis and neuroprotection effects [23,24]. More importantly, liquiritin has powerful inhibitory effects on the development of various cancers, such as gastric cancer, cervical cancer and lung cancer [25][26][27].…”

“…Liquiritin (Fig. 1A), an active component of Glycyrrhiza Radix, possesses multiple pharmacological activities including antiinflammation, neuroprotection, anti-cancer activities [23,24]. For example, liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer [25].…”

Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma

“…After 14 days, both groups were subdivided into 2 subgroups ( n = 6, respectively) and orally administrated drinking water and adenosine (30 mg/kg) for 17 days. Administration amounts of adenosine were determined based on our previous studies; 30 mg/kg for quercetin and isoliquiritigenin [44]. Tumors were identified and measured every other day using a standard caliper; tumor size was calculated using [tumor length (mm) × tumor width (mm) 2 ]/2 as previously described [21].…”