3-Epi-betulinic acid 3- O- β- D-glucopyranoside (eBAG) induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma

Abstract

Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) is a pentacyclic triterpene mainly distributed in food and medicinal plants, which exhibits various pharmacological properties. However, whether these functions are attributed to eBAG or additional components in these plants remain unknown. Herein, we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells. EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells. The eBAG-induced cell death was inhibited by knock-down of autophagy related gene (ATG) 5 and ATG7, by administration of 3-methyladenine, a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase (PI3K), and by chloroquine, a classic autophagy fl ux inhibitor. We demonstrated that eBAG induced an autophagy-mediated cell death. Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP, activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR. Co-treatment with compound C, an AMPK inhibitor, abrogated cell death induced by eBAG. We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice. As a functional food ingredient, eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.

3α-Hydroxylup-20(29)-ene-23,28-dioic Acid as a Phytogenic Chemical Marker for Authenticating Schefflera octophylla (Lour.) Harms Monofloral Honey

“…Yu et al revealed that oleanane-type triterpenoids could improve the inflammation in Raw 254.7 cells induced by 5,6-dimethylxanthenone-4-acetic acid . As for the isolated triterpenoids in this study, betulonic acid was previously identified in fruits, such as Punica granatum, Crataegus pinnatifida, Ziziphus montana, and Citrus reticulate, and has been proven to have the potential as an antileukemia stem cell chemotherapy agent; 3- eip -betulinic acid was also previously isolated and identified from Plectranthus glandulosus and has been demonstrated to have high antioxidant activity; betulinic acid 3- O -sulfate, HLEDA, and HLEDA-28- O -α- l -rhamnopyranosyl-(1 → 4)- O -β- d -glucopyranosyl-(1 → 6)-β- d -glucopyranoside showed a notable coagulation effect in vitro ; 3α,11α-dihydroxylup-20(29)-ene-23,28-dioic acid showed antineuroinflammatory activity; 3- epi -betulinic acid 3- O -β- d -glucopyranoside exhibited potential in treating hepatocellular carcinoma and esophageal cancer . Besides, HLEDA and acankoreoside A are the main triterpenoid compounds in P- Sco , which could be recognized as markers for P- Sco quality control …”

“…27 As for the isolated triterpenoids in this study, betulonic acid was previously identified in fruits, such as Punica granatum, Crataegus pinnatifida, Ziziphus montana, and Citrus reticulate, 28 and has been proven to have the potential as an antileukemia stem cell chemotherapy agent; 29 29)-ene-23,28-dioic acid showed antineuroinflammatory activity; 32 3-epi-betulinic acid 3-O-β-D-glucopyranoside exhibited potential in treating hepatocellular carcinoma and esophageal cancer. 33 Besides, HLEDA and acankoreoside A are the main triterpenoid compounds in P-Sco, which could be recognized as markers for P-Sco quality control. 10 Physicochemical Properties of MH-Sco.…”