Hydroxypyridinone-Coumarin Inhibits the Proliferation of MHCC97 and HepG2 Human Hepatocellular Carcinoma Cells and Down-Regulates the Phosphoinositide-3 Kinase Pathway

Abstract

Departmental sources Background:Worldwide, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignant diseases and is the third leading cause of cancer-related death. This study aimed to investigate the effect of hydroxypyridinone-coumarin (HPC) on MHCC97 and HepG2 human HCC cells and the mechanisms involved. Material/Methods: MHCC97 and HepG2 human HCC cells were cultured in vitro. An MTT cytotoxicity assay was used to assess cell viability and proliferation, with and without treatment with HPC. Cell autophagosomes were labeled with GFP-LC3 using confocal fluorescence microscopy. Western blot was used to measure protein expression. Results:HPC significantly reduced the cell proliferation rate in a concentration-dependent manner, with 2 µM of HPC resulting in a reduced proliferation rate of MHCC97 cells (by 36%) and HepG2 cells (by 29%) (P<0.02). HPC significantly reduced autophagy in MHCC97 and HepG2 cells. Western blot showed that treatment with HPC significant upregulated Atg5, beclin-1, LC3-phosphatidylethanolamine conjugate (LC3-II), and Atg-3, reduced p62 and Akt protein expression, and induced phosphorylation of ERK1/2. GFP-LC3B labeling in MHCC97 and HepG2 cells was increased following HPC treatment. Conclusions:HPC induced autophagy and inhibited the proliferation of MHCC97 and HepG2 HCC cells in vitro and involved activation of ERK1/2 and down-regulation of the Akt pathway.

Coumarins and Gastrointestinal Cancer: A New Therapeutic Option?

“…HPC treatment increased autophagy in MHCC97 and HepG2 cells as shown by GFP-LC3B fluorescence labeling. HPC also induced phosphorylation of ERK1/2 and led to Akt pathway downregulation (197).…”

“…Many natural compounds have been found to have anti-cancer effects by promoting autophagy (195,196). Cui et al studied HepG2 and MHCC97 (two human HCC cell lines) treated with hydroxypyridinonecoumarin (HPC) in vitro (197). The MTT cytotoxicity test assessed proliferation and viability with and without HPC treatment.…”

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies

“…The induction of autophagic cell death in prostate cancer cells (PC-3 and DU145) was also demonstrated for a geranylated 4-phenylcoumarin (DMDP-1; 9 µM), extracted from the bark of Mesua elegans (Clusiaceae) [199]. Recently, Cui et al reported that hydroxypyridinone-coumarin (2 µM) induced autophagy and thus inhibited the proliferation of HCC cells (MHCC97 and HepG2) by activating ERK1/2, by inhibiting Akt, by increasing ATG5, ATG3, Beclin 1 and LC3 II proteins and by reducing p62 levels [200]. Similarly, Li et al reported the induction of apoptosis and autophagic cell death by psoralidin (9-26 µM) leading to the inhibition of the liver cancer cell line HepG2 proliferation, as shown by the presence of autophagosomes, increase in LC3 II and Beclin 1 expression [201].…”