Modulation of DNA methylation by a sesquiterpene lactone parthenolide

Zhongfa Liu, Shujun Liu, Zhiliang Xie, Ryan E. Pavlovicz, Jiejun Wu, Ping Chen, Josephine Aimiuwu, Jiuxia Pang, Deepak Bhasin, Paolo Neviani, James R. Fuchs, Christoph Plass, Pui Kai Li, Chenglong Li, Tim H.M. Huang, Lai Chu Wu, Laura Rush, Hongyan Wang, Danilo Perrotti, Guido MarcucciKenneth K. Chan

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


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-κB 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 μM, possibly through alkylation of the proximal thiolate of Cys 1226 of the catalytic domain by its γ-methylene lactone, and 2) down-regulates DNMTI expression possibly associated with its SubG., cell-cycle arrest or the interruption of transcriptional factor Sp1 binding to the promoter of DNMTI. 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.

Original languageEnglish (US)
Pages (from-to)505-514
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - May 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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