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

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

doi:10.3389/fonc.2020.01319

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

Front Oncol. 2020 Aug 11:10:1319. doi: 10.3389/fonc.2020.01319. eCollection 2020.

Authors

Chi-Yuan Chen^{1

2}, Jia-You Fang^{3

4}, Chin-Chuan Chen^{1

3}, Wen-Yu Chuang⁵, Yann-Lii Leu^{3

6

7}, Shir-Hwa Ueng⁵, Li-Shan Wei¹, Shu-Fang Cheng^{1

3}, Chuen Hsueh^{1

5}, Tong-Hong Wang^{1

2

8}

Affiliations

¹ Tissue Bank, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.
² Graduate Institute of Health Industry Technology, Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan.
³ Graduate Institute of Natural Products, Chang Gung University, Taoyuan City, Taiwan.
⁴ Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.
⁵ Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan City, Taiwan.
⁶ Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan.
⁷ Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.
⁸ Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

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.

Keywords: 2-O-methylmagnolol (MM1); hepatocellular carcinoma (HCC); histone deacetylase (HDAC); magnolol; p21; p53.