2-O-Methylmagnolol, a Magnolol Derivative, Suppresses Hepatocellular Carcinoma Progression via Inhibiting Class I Histone Deacetylase Expression

Chi-Yuan Chen,Chuen Hsueh,Wen-Yu Chuang,Yann-Lii Leu,Li-Shan Wei,Shu-Fang Cheng,Chin-Chuan Chen,Jia-You Fang,Shir-Hwa Ueng,Tong-Hong Wang

doi:10.3389/fonc.2020.01319

Abstract

Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.

Highlights

The World Health Organization (WHO) indicated that liver cancer was the sixth most common cancer and the fourth leading cause of cancer deaths worldwide in 2018, with a global death toll of 782,000 [1]
Previous studies have reported that histone deacetylase (HDAC) overexpression is common in hepatitis B virus (HBV)-infected liver cancer patients [17, 18] and could lead to carcinogenesis, as HDACs regulate the deacetylation of histone and non-histone proteins, thereby coordinating gene expression or protein activation
Both the cell and the animal models showed that magnolol and MM1 inhibited hepatocellular carcinoma (HCC) cell and tumor growth, the inhibitory effect of MM1 was superior to that of magnolol at similar concentrations

Summary

INTRODUCTION

The World Health Organization (WHO) indicated that liver cancer was the sixth most common cancer and the fourth leading cause of cancer deaths worldwide in 2018, with a global death toll of 782,000 [1]. Previous studies have reported that histone deacetylase (HDAC) overexpression is common in hepatitis B virus (HBV)-infected liver cancer patients [17, 18] and could lead to carcinogenesis, as HDACs regulate the deacetylation of histone and non-histone proteins, thereby coordinating gene expression or protein activation. Class I HDAC overexpression can inhibit the expression of multiple tumor-suppressor genes, such as p21 and p53, thereby promoting carcinogenesis [25,26,27] These HDACs are therapeutic targets for multiple anticancer treatments. Owing to the development of component separation technologies, the active ingredients of traditional Chinese medicines have been extracted and their functions identified These compounds can act at lower effective doses and produce more specific therapeutic effects. In addition to testing the anti-hepatocellular carcinoma (HCC) activities of magnolol and its derivative MM1, we used cell and animal models to clarify their modes of action, thereby elucidating the feasibility of their clinical applications

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT