Tumor Inhibitory Agent from Magnolia grandiflora (Magnoliaceae) I: Parthenolide

Wiedhopf, Richard M.; Young, Maria Cláudia Marx; Bianchi, E.; Cole, Jack R.

doi:10.1002/jps.2600620244

Cited by 58 publications

(30 citation statements)

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“…12 More recently, PTL has been found to have several other properties, including antitumor activity, inhibition of DNA synthesis, and inhibition of cell proliferation in different cancer cell lines. [13][14][15][16] In addition, PTL sensitizes cancer cells to other antitumor agents [17][18][19][20] and acts as a chemopreventive agent in a UVB-induced skin cancer animal model. 21 PTL is a potent inhibitor of NF-B activation and has been shown to directly bind IB-kinase (IKK) 22,23 and to modify the p50 and p65 NF-B subunits.…”

Section: Introductionmentioning

confidence: 99%

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells

Guzmán

Rossi

Karnischky

et al. 2005

Blood

631

580

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Section: Introductionmentioning

confidence: 99%

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells

Guzmán

Rossi

Karnischky

et al. 2005

Blood

631

580

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“…Parthenolide (PTL), a sesquiterpene lactone isolated from feverfew (Tanacetum parthenium) by extraction from its leaves and stems, is the principal ingredient of the medicinal herb Magnolia grandiflora L (1) and has also been reported to have antitumor activity (2)(3)(4). We previously found that combination therapy with PTL and heating at 40, 42 or 44˚C showed synergistic thermosensitization effects on human lung adenocarcinoma A549 cells with wtp53, which resulted in p53-and hsp72-independent apoptosis induction via the nuclear factor-κB (NF-κB) signal pathway (5).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Hayashi

Sakurai²,

Hayashi³

et al. 2009

Int J Mol Med

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Abstract. We investigated the mechanisms of thermosensitization related to combination therapy with sesquiterpene lactone parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, and hyperthermia using human lung adenocarcinoma cells A549. The kinetics of apoptosis induction and cell cycle of cells treated with PTL, heating, and combined treatment were examined by flow cytometric analysis. The flow cytometric distribution was calculated and expressed as a percentage. The ratios of the sub-G 1 division, used to determine the induction of apoptosis, increased significantly with the combination therapy. Furthermore, the ratios of G 2 /M division increased and the ratios of G 0 /G 1 division decreased, indicating cell cycle arrest in G 2 /M. The cell phase response to PTL by A549 cells synchronized in the G 1 /S border with hydroxyurea was also analyzed. PTL showed remarkable cytotoxicity at the S phase of the cell cycle in A549 cells at all concentrations as well as with hyperthermia, thus PTL reduced the number of cells in the proliferation phase. Inhibition of intracellular transcription factor NF-κB activation in A549 cells with various incubation periods after treatments with PTL, heating and combined treatment was examined by Western blot analysis. Unexpectedly, PTL alone did not inhibit NF-κB activation in cells stimulated with TNF-·, while heating alone inhibited NF-κB early after treatment and that effect faded over time. In contrast, PTL combined with heating completely inhibited NF-κB activation. Our results demonstrated that PTL and heating in combination cause significant thermosensitization of A549 cells via induction of apoptosis or cell cycle arrest in G 2 /M by inhibiting NF-κB activation in a synergistic manner.

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“…Because of inhibition activity to nuclear transcription factor (NF-B), this compound has been tested for anti-cancer activities, with encouraging results both in in vitro and in vivo (Wiedhopf et al, 1973;Woynarowski and Konopa, 1981;Patel et al, 2000;García-Piñ eres et al, 2001Nakshatri et al, 2004;Won et al, 2004;Guzman et al, 2005;Steele et al, 2006). Mechanistic studies demonstrated that parthenolide covalently blocks the thiol group of cysteine at the active site of p65 NF-B through its highly electrophilic ␥-methylene lactone ring.…”

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confidence: 99%

Modulation of DNA Methylation by a Sesquiterpene Lactone Parthenolide

Liu

Xie

et al. 2009

J Pharmacol Exp Ther

127

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Hypermethylation of 5Ј-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-B 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 M, possibly through alkylation of the proximal thiolate of Cys 1226 of the catalytic domain by its ␥-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.DNA methylation of cytosine residues in the context of the sequence 5Ј-cytosine-guanosine (CpG) in gene promoter regions is an epigenetic mechanism that controls gene transcription, genome stability, and genetic imprinting (Robertson, 2005). This process is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosyl-methionine (SAM) that serves as a methyl donor for methylation of cytosine residues at the C-5 position to yield 5-methylcytosine (Robertson, 2005). Aberrant hypermethylation of promoter CpG-rich regions (Ͼ55% CG content, the so-called CpG islands) of tumor suppressor genes (TSGs) results in transcriptional silencing in a variety of solid tumors and blood cancers (Yoo and Jones, 2006). In vitro and in vivo treatment with DNA methyl-

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Tumor Inhibitory Agent from Magnolia grandiflora (Magnoliaceae) I: Parthenolide

Cited by 58 publications

References 1 publication

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Modulation of DNA Methylation by a Sesquiterpene Lactone Parthenolide

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