Glycyrrhizic Acid Suppresses the Development of Precancerous Lesions via Regulating the Hyperproliferation, Inflammation, Angiogenesis and Apoptosis in the Colon of Wistar Rats

Abstract

BackgroundColon carcinogenesis is a multistep process and it emanates from a series of molecular and histopathological alterations. Glycyrrhizic acid (GA) is a natural and major pentacyclic triterpenoid glycoside of licorice roots extracts. It has several pharmacological and biological properties such as anti-inflammatory, anti-viral, and anti-cancer. In the present study, we investigated the chemopreventive potential of GA against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions i.e., aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats.MethodsAnimals were divided into 5 groups. In group III, IV and V, GA was administered at the dose of 15 mg/kg b. wt. orally while in group II, III and IV, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b.wt once a week for first 5 weeks and animals were euthanized after 9 weeks.ResultsGA supplementation suppressed the development of precancerous lesions and it also reduced the infiltration of mast cells, suppressed the immunostaining of Ki-67, NF-kB-p65, COX-2, iNOS and VEGF while enhanced the immunostaining of p53, connexin-43, caspase-9 and cleaved caspase-3. GA treatment significantly attenuated the level of TNF-α and it also reduced the depletion of the mucous layer as well as attenuated the shifting of sialomucin to sulphomucin.ConclusionOur findings suggest that GA has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of GA.

Chemopreventive Effects of Licorice and Its Components

“…A more recent study indicated that GA supplementation suppressed the development of 1,2-dimethyhydrazine (DMH)-induced precancerous lesions in Wistar rat colon. It also reduced the infiltration of mast cells, attenuated the expression of Ki-67, NF-κB/ p65, COX-2, inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF), while enhancing the expression of p53, connexin-43, caspase-9, and cleaved caspase-3, which suggested the induction of apoptosis [43], also agreeing with other studies [29,42]. GA reportedly induced G0/G1 phase arrest, apoptosis, and DNA damage in WEHI-3 leukemia cells by increasing reactive oxygen species (ROS) levels and caspase-3 activity in these cells [44].…”

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

“…Grape seed extract, a rich source of polyphenols and Yerba mate Tea both inhibits iNOS expression by modulating its upstream target NF-κB in AOM-induced colon cancer (Derry et al, 2013;Puangpraphant et al, 2013). Glycyrrhizic acid is natural and major pentacyclictriterpenoid glycosides of licorice roots extracts suppress the precancerous lesions by modulating iNOS expression in colon cancer (Khan et al, 2013). Resveratrol, a polyphenol abundantly found in grapes and red wine, exhibits beneficial health effects due to its anti-inflammatory properties by modulating iNOS expression in Caco-2 and SW480 colon cancer cell lines (Panaro et al, 2012).…”

“…Diallyl sulfide, a garlic derived organo sulphur compound induces apoptosis mediated through the activation of caspase (Sriram et al, 2008). Quercetin enhances hypoxiamediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer (Kim et al, 2012). Luteolin, a bioflavonoid induce apoptosis via modulating the expressions of Bcl-2, Bax and caspase-3 in vivo and in vitro Pandurangan and Ganapsam, 2013).…”

Treatment of Hematological Malignancies with Glycyrrhizic Acid

“…There is a number of reports demonstrating anticancer properties of GA. Specifically, GA has been shown to be effective at inhibiting the growth of colon cancer, glioblastoma, lung cancer, melanoma, and ovarian cancer cell lines (6,(14)(15)(16)(17)(18). In addition, glycyrrhetic acid, a derivative of GA, is active against human hepatoma, promyelotic leukemia, and stomach cancer cell lines in vitro (8).…”

“…GA has been shown to be effective against a number of cancers including, but not limited to colon cancer, glioblastoma, lung cancer, leukemia, and melanoma (6,(14)(15)(16)(17)(18). Furthermore, GA was shown to clinically reduce the incidence of liver carcinogenesis in patients with hepatitis C (19).…”