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.
Highlights
Licorice is the root of Glycyrrhiza glabra or Glycyrrhiza uralensis, a perennial legume found in southern Europe (Glycyrrhiza glabra) and in east Asia (Glycyrrhiza uralensis)
We examined the anti-cancer effects of quercetin and isoliquiritigenin in in vivo xenograft models implanted with Epstein-Barr virus (EBV)(+) human gastric carcinoma (SNU719) or EBV(−) human gastric carcinoma (MKN74)
We explored the molecular mechanisms responsible for the anti-cancer activities of quercetin and isoliquiritigenin using tumor tissues derived from in vivo xenograft animals implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(−) human gastric carcinoma (MKN74)
Summary
Licorice is the root of Glycyrrhiza glabra or Glycyrrhiza uralensis, a perennial legume found in southern Europe (Glycyrrhiza glabra) and in east Asia (Glycyrrhiza uralensis). Glycyrrhiza contains a diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and the flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin) [1]. The flavonoids of licorice include quercetin, isoliquiritigenin, and liquiritin, and all three have been shown to have strong anti-cancer activity [2]. Isoliquiritigenin has been reported to stimulate cell cycle arrest in human prostate cancer cells and to induce the death of human breast cancer and gastric cancer cells [3,4,5]. Isoliquiritigenin was found to suppress human lung cancer cell growth and colon cancer in mice [6]. These observations suggest isoliquiritigenin has great potential for cancer prevention and therapy. The anti-viral effects of isoliquiritigenin have only been reported by a few studies. Sekine-Osajima et al and Adianti et al found isoliquiritigenin strongly inhibits Hepatitis C virus (HCV) replication [7,8]
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