title: Modulation of DNA methylation by a sesquiterpene lactone parthenolide.
abstract: Hypermethylation of 5'-cytosine-guanosine islands of tumor suppressor genes resulting in their silencing has been proposed to be a hallmark of various tumors. Modulation of DNA methylation with DNA methylation inhibitors has been shown to result in cancer cell differentiation or apoptosis and represents a novel strategy for chemotherapy. Currently, effective DNA methylation inhibitors are mainly limited to decitabine and 5-azacytidine, which still show unfavorable toxicity profiles in the clinical setting. Thus, discovery and development of novel hypomethylating agents, with a more favorable toxicity profile, is essential to broaden the spectrum of epigenetic therapy. Parthenolide, the principal bioactive sesquiterpene lactone of feverfew, has been shown to alkylate Cys(38) of p65 to inhibit nuclear factor-kappaB activation and exhibit anti-tumor activity in human malignancies. In this article, we report that parthenolide 1) inhibits DNA methyltransferase 1 (DNMT1) with an IC(50) of 3.5 microM, possibly through alkylation of the proximal thiolate of Cys(1226) of the catalytic domain by its gamma-methylene lactone, and 2) down-regulates DNMT1 expression possibly associated with its SubG(1) cell-cycle arrest or the interruption of transcriptional factor Sp1 binding to the promoter of DNMT1. These dual functions of parthenolide result in the observed in vitro and in vivo global DNA hypomethylation. Furthermore, parthenolide has been shown to reactivate tumor suppressor HIN-1 gene in vitro possibly associated with its promoter hypomethylation. Hence, our study established parthenolide as an effective DNA methylation inhibitor, representing a novel prototype for DNMT1 inhibitor discovery and development from natural structural-diversified sesquiterpene lactones.
authors.affiliation: Division of Pharmaceutics, Colleges of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Xie
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Josephine
authors.initials: J
authors.lastname: Aimiuwu
authors.forename: Jiuxia
authors.initials: J
authors.lastname: Pang
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhasin
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.forename: Laura
authors.initials: L
authors.lastname: Rush
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
mesh_terms: D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003545:Cysteine / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016329:Sp1 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007783:Lactones; C434732:SCGB3A1 protein, human; D012717:Sesquiterpenes; D016329:Sp1 Transcription Factor; D025521:Tumor Suppressor Proteins; C002669:parthenolide; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D003545:Cysteine