Ginsenoside Rg3 Prolongs Survival of the Orthotopic Hepatocellular Carcinoma Model by Inducing Apoptosis and Inhibiting Angiogenesis

Abstract

Aim. Microvessel density is a marker of tumor angiogenesis activity for development and metastasis. Our preliminary study showed that ginsenoside Rg3 (Rg3) induces apoptosis in hepatocellular carcinoma (HCC) in vitro. The aim of this study was to investigate the cross-link for apoptosis induction and antiangiogenesis effect of Rg3 on orthotopic HCC in vivo. Methods. The murine HCC cells Hep1-6 were implanted in the liver of mouse. With oral feeding of Rg3 (10 mg/kg once a day for 30 days), the quantitative analysis of apoptosis was performed by using pathology and a transmission electron microscope and microvessel density was quantitatively measured by immunohistochemical staining of the CD105 antibody. The mice treated with Rg3 (n=10) were compared with the control (n=10) using Kaplan-Meier analysis. Animal weight and tumor weight were measured to determine the toxicity of Rg3 and antitumor effect on an orthotopic HCC tumor model. Results. With oral feeding of Rg3 daily in the first 30 days on tumor implantation, Rg3 significantly decreased the orthotopic tumor growth and increased the survival of animals (P<0.05). Rg3-treated mice showed a longer survival than the control (P<0.05). Rg3 treatment induced apoptosis and inhibited angiogenesis. They contributed to the tumor shrinkage. Rg3 initialized the tumor apoptotic progress, which then weakened the tumor volume and its capability to produce the vascularized network for further growth of the tumor and remote metastasis. Conclusion. Rg3 inhibited the activation of microtumor vessel formation in vivo besides its apoptosis induction. Rg3 may be used as an adjuvant agent in the clinical HCC treatment regimen.

Chinese Herbal Medicine for Primary Liver Cancer Therapy: Perspectives and Challenges

“…In vivo studies have revealed that direct targeted inhibition of VEGF by ginsenoside Rg3 in combination with TACE blocked angiogenesis and tumor growth, eventually reducing the tumor size and metastasis and prolonging OS in a buffalo rat orthotopic liver cancer model and rabbit liver VX2 carcinoma models ( Yu et al, 2013 ; Zhou et al, 2014 ). The inhibitory effect of ginsenoside Rg3 on tumor MVD was also observed in C57BL/6 mice implanted with Hepa1-6 cells, and ginsenoside Rg3 initiated apoptosis of the tumor cells ( Li et al, 2018 ), decreased the tumor volume and ability of the tumor to generate vascularized networks, and inhibited further growth and remote metastasis ( Hu et al, 2019 ). Ginsenoside Rg3 has shown good antitumor activity in vivo and is well tolerated without significant toxic side effects, but it has low water solubility and poor oral bioavailability, which affect clinical applications.…”

Phytochemicals as an Alternative or Integrative Option, in Conjunction with Conventional Treatments for Hepatocellular Carcinoma

“…Moreover, ginsenoside Rg3 reduces phosphorylation of STAT3 resulting from hypoxic conditions, phosphorylation of ERK 1/2, JNK, and decreases VEGF expression [168]. Ginsenoside Rg3 was shown to inhibit microtumor vessel formation activation in mice when given at a dose of 10 mg/kg once a day and it contributed to tumor shrinkage and increased animal survival [169]. A study that assessed the pharmacokinetics of Ginsenoside Rg3 found that it was well tolerated by humans when administered intramuscularly at a dose ranging from 10-60 mg once every two days [170].…”

Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway

“…Ginsenoside Rg3 (Rg3) is a terpenoid and an active component of ginseng, which can affect multiple metabolic pathways and play a variety of roles in the body, such as repairing damage and anti-tumor and anti-oxidation effects [ 11–13 ]. Recently, several studies have confirmed that Rg3 effectively inhibits HCC progression [ 14 , 15 ]. However, the role of Rg3 and SFN combination therapy in HCC remains unclear.…”