title: Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells by inhibition of DNA methyltransferase.
abstract: Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non-small-cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A, APC, RUNX3, and p16INK4, which in turn activates their mediated pro-apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1.
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Xin-Zhi
authors: XZ
authors: Wang
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Ying
authors: Y
authors: Cheng
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Kui-Long
authors: KL
authors: Wang
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Rui
authors: R
authors: Liu
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Xiao-Lin
authors: XL
authors: Yang
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Hong-Mei
authors: HM
authors: Wen
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Chuan
authors: C
authors: Chai
authors: Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
authors: Jing-Yu
authors: JY
authors: Liang
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. whao5795@vip.sina.com.
authors: Hao
authors: H
authors: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; C545363:peperomin E; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: Anticancer activity; DNA (cytosine-5-)-methyltransferase 1; non-small-cell lung cancer; peperomin E; tumor suppressor genes