Gundelia Tournefortii Extracts Inhibit Progressions of Hepatocellular Carcinoma in Mice Model Through Decrease in p53/Akt/PI3K Signaling Pathway

Abstract

Background: Gundelia (G.) tournefortii is one of the most famous plants used in Palestine for its traditional curative and nutritive properties. We evaluated effects of Gundelia (G.) tournefortii aqueous-extract in an ex-vivo and in in-vivo animal model of hepatocellular carcinoma (HCC).Methods: HCC cell-line (Hep3B) were injected in the back of male mice on NOD.CB17-Prkdc-scid/NCrHsD background. Tumor size, serum a-fetoprotein (αFP) and Glypican-3 (GPC3) were assessed at day 2 following HCC injections till day-12. G. tournifortii extracts were injected i.p at day 10 in HCC mice. Liver histology, hepatic-p53, p-Akt and p-PI3K expressions were evaluated. Primary-hepatocytes from HCC mice were ex-vivo treated with G. tournifortii and investigated for perturbation of the DNA cell cycle using propidium iodide (PI) staining assay, while apoptosis was estimated by staining with Annexin-V and PI by the flow cytometry.Results: Tumor mass increase in animals with HCC and was associated with elevated aFP and GPC3 (P<0.05). Mice receiving G. tournefortii extracts showed a significant decrease in tumor at days 12 with decreased hepatic-p53 and phosphorylated Akt/PI3K signaling pathway (p=0.001). Histology H&E staining showed remarkable reduction in inflammatory lesions in HCC livers receiving G. tournifortii extracts in line with delay in G2-M phase of HCC-primary-hepatocytes to 1.39-folds. Moreover, apoptotic activity was mostly enhanced by the 200mg/ml G. tournifortii extracts while a reduction of HCC necrosis to 2.4 fold (P<0.01).Conclusions: Our results explored an anti-cancer, anti-proliferative and apoptotic effects of G. tournifortii in an HCC mice model and in an ex-vivo setting. G. tournifortii could be a promising future cancer remedy.

A Review of the Ethnobotany, Biological Activity, and Phytochemistry of the Plants in the Gundelia Genus

“…[57] In other studies on the analgesic and anti-inflammatory potentials of G. tournefortii, the presence of various compounds, including scopoletin, stigmasterol, sitosterol, and phenolic compounds, was suggested to be responsible for the observed effects (Table 3). [135] extracts, ethyl acetate and n-butanol extracts exhibited hepatoprotective effects as judged by lower AST, ALT, LDH, and lipid peroxidation, prevention of tissue glutathione depletion, and alleviation of histopathological liver damage in the extracttreated animals. [138] Another study evaluated the effects of G. tournefortii 70 % aqueous/ethanol extract on ALT, AST, and ALP in a carbon tetrachloride-induced hepatotoxicity model.…”

“…[57] In another study, an 80 % hydroalcoholic extract of G. tournefortii was injected intraperitoneally into NMRI mice, and the median lethal dose was reported as LD 50 = 6.28 g/kg. [135]…”

Germination and <i>in vitro</i> Propagation of <i>Gundelia tournefontii</i> an Important Medicinal Plant

“…In traditional medication, the plant shoot is a well-thought-out hepatoprotective and blood purifier (Asadi-Samani et al, 2013; Amer et al, 2020) The G. tournefortii extract was reported to decrease the plasma lipid level and contains phenolic compounds such as quercetin with powerful antioxidant effects (Apak et al, 2007;Alimoradi et al, 2017). The edible parts of G. tournefortii are a rich source of minerals and vitamins C, B, and A and have been therapeutically used in the old medication system (Karimi et al, 2004;Askari et al, 2008;Tabibian et al, 2013).…”

“…The G. tournefontii plants have a thick perennial rootstock, from which new growth ascends each season. G. tournefortii is a "spiny thistle-like perennial plant about 60 cm height, and its stems branch from the base and almost hairless" (Amer et al, 2020). The usage of this plant is possibly quite old.…”