| Title | Modulation of DNA methylation by a sesquiterpene lactone parthenolide. | | Author(s) | Liu Z, Liu S, Xie Z, Pavlovicz RE, Wu J, Chen P, Aimiuwu J, Pang J, Bhasin D, Neviani P, Fuchs JR, Plass C, Li PK, Li C, Huang TH, Wu LC, Rush L, Wang H, Perrotti D, Marcucci G, Chan KK | | Institution | Division of Pharmaceutics, Colleges of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. | | Source | J Pharmacol Exp Ther 2009 May; 329(2):505-14. | | MeSH | Alkylation
Animals
Antineoplastic Agents
Apoptosis
Catalytic Domain
Cell Cycle
Cell Line, Tumor
Cell Survival
Chromatin Immunoprecipitation
Cysteine
Cytokines
DNA (Cytosine-5-)-Methyltransferase
DNA Methylation
Electrophoretic Mobility Shift Assay
Female
Humans
Immunoblotting
Lactones
Mice
Mice, Nude
Models, Molecular
Neoplasms
Promoter Regions, Genetic
Sesquiterpenes
Sp1 Transcription Factor
Tumor Suppressor Proteins
Xenograft Model Antitumor Assays
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19201992 |
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