TY - JOUR
T1 - Modulation of DNA methylation by a sesquiterpene lactone parthenolide
AU - Liu, Zhongfa
AU - Liu, Shujun
AU - Xie, Zhiliang
AU - Pavlovicz, Ryan E.
AU - Wu, Jiejun
AU - Chen, Ping
AU - Aimiuwu, Josephine
AU - Pang, Jiuxia
AU - Bhasin, Deepak
AU - Neviani, Paolo
AU - Fuchs, James R.
AU - Plass, Christoph
AU - Li, Pui Kai
AU - Li, Chenglong
AU - Huang, Tim H.M.
AU - Wu, Lai Chu
AU - Rush, Laura
AU - Wang, Hongyan
AU - Perrotti, Danilo
AU - Marcucci, Guido
AU - Chan, Kenneth K.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=65649091667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65649091667&partnerID=8YFLogxK
U2 - 10.1124/jpet.108.147934
DO - 10.1124/jpet.108.147934
M3 - Article
C2 - 19201992
AN - SCOPUS:65649091667
SN - 0022-3565
VL - 329
SP - 505
EP - 514
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -