Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer.
Histone modifications play critical roles in the progression of non-small cell lung cancer (NSCLC), which accounts for almost 85% of all diagnosed lung cancers. Magnolol and polyphenol mixture (PM) derived from Magnolia officinalis exhibited remarkable antitumor activities in lung cancer. However, the epigenetic effects and molecular mechanisms of magnolol and PM in NSCLC have yet to be reported. In this study, the epigenetic effects of magnolol and PM in NSCLC were examined in vitro and in vivo. Results revealed that magnolol and PM significantly suppressed the expression levels and function of class I histone deacetylases (HDACs). In A549 and H1299 cells, magnolol and PM remarkably induced cell apoptosis by arresting the cell cycle in the G0/G1 phase while simultaneously activating various pro-apoptotic signals, including TRAIL-R2 (DR5), Bax, caspase 3, cleaved caspase 3, and cleaved PARP. However, these apoptosis-promoting effects could be attenuated by TSA, which is a specific class I HDACs inhibitor. ChIP assays also demonstrated that magnolol and PM significantly enriched the histone acetyl mark (H3K27ac) in the promoter region of DR5. In A549 xenograft model, magnolol and PM notably reduced tumor growth by 44.40% and 35.40%, respectively. Therefore, magnolol and PM, as potential inhibitors of class I HDACs, induced tumor cell apoptosis and suppressed tumor growth partially by epigenetically activating DR5, which is a key protein in death receptor signaling pathway.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Yuting
Y
Liu
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Yunli
Y
Tong
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Xia
X
Yang
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Fangyuan
F
Li
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Liang
L
Zheng
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Wenqin
W
Liu
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Jinjun
J
Wu
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Rilan
R
Ou
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Guiyu
G
Zhang
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA.
Ming
M
Hu
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: liuzq@gzucm.edu.cn.
Zhongqiu
Z
Liu
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China. Electronic address: lllu@gzucm.edu.cn.
Linlin
L
Lu
D000072283:A549 Cells; D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001713:Biphenyl Compounds / Q000302:isolation & purification / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D031566:Magnolia / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008517:Phytotherapy; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D059808:Polyphenols / Q000302:isolation & purification / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017705:Lignans; D010936:Plant Extracts; D059808:Polyphenols; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C005498:magnolol; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
Histone deacetylase; Honokiol (PubChem CID: 72303); Magnolol; Magnolol (PubChem CID: 72300); Non-small cell lung cancer; Obovatol (PubChem CID: 100771); Polyphenol mixture; TRAIL