Parthenolide

1 Tanacetum sp.

Parthenolide is an NF-κB inhibitor, reduces histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1 independent of NF-κB inhibition.

In Vitro:Parthenolide (PTL) has a dose-dependent growth inhibition effect on NSCLC cells Calu-1, H1792, A549, H1299, H157, and H460. Parthenolide can induce cleavage of apoptotic proteins such as CASP8, CASP9, CASP3 and PARP1 both in concentration- and time-dependent manner in tested lung cancer cells, indicating that apoptosis is trigged after Parthenolide exposure. In addition to induction of apoptosis, Parthenolide also induces G0/G1 cell cycle arrest in a concentration-dependent manner in A549 cells and G2/M cell cycle arrest in H1792 cells[2].

In Vivo:Only Parthenolide, the HDAC inhibitor with anti-inflammatory features, displayed a potent anti-apoptotic effect in Phb1 KO hepatocytes. Indeed, TSA and Parthenolide-treated hepatocytes showed increased levels of FXR, and reduced levels of CYP7A1, HDAC4, TNFα, TRAIL and Bax suggesting a less toxic effect of bile acids as a results of specific HDAC inhibition, resulting in the attenuation of the Phb1 KO hepatocytes apoptotic response. Importantly, Parthenolide exerts a protective effect from the liver injury after BDL in Phb1 KO mice. Indeed, Parthenolide treatment results in a reduction of the mortality rate of this mice after BDL associated with a lower apoptotic response as revealed by a reduction of necrotic areas, Tunel-staining, as well as decreased ALT (8431±957 vs.4225±210 U/L) and AST (4805±300 vs.2242±438 U/L) activities compared to control Phb1 KO mice[3].

References:
[1]. Nakshatri H, et al. NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. Cell Death Dis. 2015 Jan 22;6:e1608. [2]. Zhao X, et al. Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells. J Exp Clin Cancer Res. 2014 Jan 6;33:3. [3]. Barbier-Torres L, et al. Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin-1. Hepatology. 2015 Oct;62(4):1237-48.

Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents.[Pubmed:11961112]

Mol Pharmacol. 2002 May;61(5):953-63.

Parthenolide is a sesquiterpene lactone used in folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (NF)-kappaB pathway. This study examines the effect of Parthenolide in endotoxic shock in rodents. Endotoxic shock was induced by administration of Escherichia coli endotoxin in rats. Three groups of rats received Parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another group received Parthenolide (1 mg/kg) 3 h after endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased mRNA expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor kappaBalpha (IkappaBalpha) and activation of nuclear NF-kappaB in the lung. In vivo pretreatment and post-treatment with Parthenolide improved the hemodynamic profile and reduced plasma nitrate/nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with Parthenolide also abolished nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS mRNA content in thoracic aortas. DNA binding of NF-kappaB was inhibited by Parthenolide in the lung, whereas degradation of IkappaBalpha was unchanged. In a separate set of experiments, pretreatment or post-treatment with Parthenolide significantly improved survival in mice challenged with endotoxin. We conclude that Parthenolide exerts beneficial effects during endotoxic shock through inhibition of NF-kappaB.

Parthenolide inhibits osteoclast differentiation and bone resorbing activity by down-regulation of NFATc1 induction and c-Fos stability, during RANKL-mediated osteoclastogenesis.[Pubmed:24314143]

BMB Rep. 2014 Aug;47(8):451-6.

Parthenolide, a natural product derived from Feverfew, prevents septic shock and inflammation. We aimed to identify the effects of Parthenolide on the RANKL (receptor activator of NF-kappaB ligand)-induced differentiation and bone resorbing activity of osteoclasts. In this study, Parthenolide dose-dependently inhibited RANKL-mediated osteoclast differentiation in BMMs, without any evidence of cytotoxicity and the phosphorylation of p38, ERK, and IkappaB, as well as IkappaB degradation by RANKL treatment. Parthenolide suppressed the expression of NFATc1, OSCAR, TRAP, DC-STAMP, and cathepsin K in RANKL-treated BMMs. Furthermore, Parthenolide down-regulated the stability of c-Fos protein, but could not suppress the expression of c-Fos. Overexpression of NFATc1 and c-Fos in BMMs reversed the inhibitory effect of Parthenolide on RANKL-mediated osteoclast differentiation. Parthenolide also inhibited the bone resorbing activity of mature osteoclasts. Parthenolide inhibits the differentiation and bone-resolving activity of osteoclast by RANKL, suggesting its potential therapeutic value for bone destructive disorders associated with osteoclast-mediated bone resorption.

Parthenolide attenuates LPS-induced fever, circulating cytokines and markers of brain inflammation in rats.[Pubmed:22004922]

Cytokine. 2011 Dec;56(3):739-48.

Parthenolide, a sesquiterpene lactone, has been reported to exhibit a variety of anti-inflammatory and immunomodulatory effects. To test the effect of Parthenolide on brain inflammatory responses, brain oxidative stress and fever, we treated rats with Parthenolide (1 mg/kg), simultaneously or 1 h prior to a systemic (i.p.) challenge with a moderate dose (100 mug/kg) of lipopolysaccharide (LPS). The initial hypothermia was exaggerated; the second phase of the biphasic LPS-induced fever and circulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) were significantly attenuated only in Parthenolide-pretreated animals. In the hypothalamus, markers of NFkappaB/NF-IL6 pathway activation (inhibitor kappaBalpha, NF-IL6 and the serin/threonin kinase-like protein mRNA expression) and markers of oxidative stress (including nuclear respiratory factor 1) and NFkappaB immunoreactivity were significantly reduced while NF-IL6 immunoreactivity and suppressor of cytokine signaling 3 mRNA expression remained unaltered, 8 h after LPS-stimulation with Parthenolide-pretreatment. Importantly, this response was accompanied by decreased mRNA expression of the rate limiting enzyme in prostaglandin synthesis, cyclooxygenase 2 (COX2), known for its critical role in fever induction pathways. A direct action of Parthenolide on brain cells was also confirmed in a primary neuro-glial cell culture of the vascular organ of the lamina terminalis a pivotal brain structure for fever manifestation with a leaky blood-brain barrier. In summary, pretreatment with Parthenolide attenuates the febrile response during LPS-induced systemic inflammation by reducing circulating IL-6 and TNFalpha and decreasing hypothalamic NFkappaB/NF-IL6 activation, oxidative stress and expression of COX2. Thus Parthenolide appears to have the potential to reduce brain inflammation.

Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines.[Pubmed:25289524]

Pharm Biol. 2015 Jan;53(1):104-9.

CONTEXT: Parthenolide (a sesquiterpene lactone), a bioactive compound of Tanacetum parthenium (L.) Schultz Bip. (Asteraceae) herb, has been reported for antioxidant and anticancer activities. OBJECTIVE: The present study evaluated the effect of Parthenolide on growth and apoptosis-regulatory genes of human cervical cancer (SiHa) and breast cancer (MCF-7) cell lines. MATERIALS AND METHODS: The cytotoxic activity of Parthenolide (3.5-21 microM) was examined by MTT and LDH assays at 24 and 48 h time intervals. Apoptotic activity was evaluated by expression analysis of multiple apoptosis-regulatory genes (i.e., p53, Bcl-2, Bax, caspase-3, -6, and -9) by reverse transcriptase-PCR and DNA fragmentation assay. RESULTS: Parthenolide inhibited the growth of SiHa and MCF-7 cell lines in a concentration-dependent manner at 24 and 48 h time intervals (p < 0.001). The IC50 value of Parthenolide against SiHa and MCF-7 cells were 8.42 +/- 0.76 and 9.54 +/- 0.82 muM, respectively. Parthenolide-treated cells showed up-regulation of p53, Bax, caspase-3, -6, and -3 genes and down-regulation of Bcl-2 gene (p Parthenolide-treated cells showed the signs of apoptosis. CONCLUSION: Our study endorsed the biological activity of Parthenolide and demonstrated the Parthenolide-induced growth inhibition and apoptosis in SiHa and MCF-7 cells by modulating the expression of apoptosis-regulatory genes.

Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel.[Pubmed:23933184]

Pain. 2013 Dec;154(12):2750-8.

Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, Parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that Parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, Parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of Parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by Parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of Parthenolide.

Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium.[Pubmed:15616293]

Antimicrob Agents Chemother. 2005 Jan;49(1):176-82.

The in vitro activity of Parthenolide against Leishmania amazonensis was investigated. Parthenolide is a sesquiterpene lactone purified from the hydroalcoholic extract of aerial parts of Tanacetum parthenium. This isolated compound was identified through spectral analyses by UV, infrared, (1)H and (13)C nuclear magnetic resonance imaging, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple-quantum coherence), and electron spray ionization-mass spectrometry. Parthenolide showed significant activity against the promastigote form of L. amazonensis, with 50% inhibition of cell growth at a concentration of 0.37 microg/ml. For the intracellular amastigote form, Parthenolide reduced by 50% the survival index of parasites in macrophages when it was used at 0.81 microg/ml. The purified compound showed no cytotoxic effects against J774G8 macrophages in culture and did not cause lysis in sheep blood when it was used at higher concentrations that inhibited promastigote forms. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis with gelatin as the substrate showed that the enzymatic activity of the enzyme cysteine protease increased following treatment of the promastigotes with the isolated compound. This finding was correlated with marked morphological changes induced by Parthenolide, such as the appearance of structures similar to large lysosomes and intense exocytic activity in the region of the flagellar pocket, as seen by electron microscopy. These results provide new perspectives on the development of novel drugs with leishmanicidal activities obtained from natural products.

Inhibition of AMPK/autophagy potentiates parthenolide-induced apoptosis in human breast cancer cells.[Pubmed:24619908]

J Cell Biochem. 2014 Aug;115(8):1458-66.

Parthenolide is the main bioactive component in feverfew, a common used herbal medicine, and has been extensively studied in relation to its anti-cancer properties. However there have been very few in-depth studies of the activities of this compound at the molecular level. Here, we showed that Parthenolide increased reactive oxygen species (ROS), induced cell death, activated AMPK and autophagy, and led to M phase cell cycle arrest in breast cancer cells. Removal of ROS inhibited all Parthenolide-associated events, such as cell death, AMPK activation, autophagy induction, and cell cycle arrest. Blockade of autophagy relieved cell cycle arrest, whereas inhibition of AMPK activity significantly repressed the induction of both autophagy and cell cycle arrest. These observations clearly showed that Parthenolide-driven ROS activated AMPK-autophagy pathway. Furthermore, inhibition of either AMPK or autophagy significantly potentiated Parthenolide-induced apoptosis. Therefore, our results show that Parthenolide activates both apoptosis pathway and AMPK-autophagy survival pathway through the generation of ROS, and that suppression of AMPK or autophagy can potentially enhance the anti-cancer effect of Parthenolide on breast cancer cells.

Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components.[Pubmed:1319159]

Biochem Pharmacol. 1992 Jun 9;43(11):2313-20.

Leaves or infusions of feverfew, Tanacetum parthenium, have long been used as a folk remedy for fever, arthritis and migraine, and derived products are widely available in U.K. health food shops. Previous reports have suggested interactions with arachidonate metabolism. Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Isolated lactones (Parthenolide, epoxyartemorin) treated with cysteine (to neutralize reactive alpha-methylene butyrolactone functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not time-dependent. We conclude that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb.

A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro.[Pubmed:1981582]

J Pharm Pharmacol. 1990 Aug;42(8):553-7.

Extracts of the herb feverfew inhibit human blood platelet aggregation and secretion induced by a number of agents in-vitro and this may relate to the beneficial effects of feverfew in migraine. We previously identified several compounds with antisecretory activity in human blood platelets using adrenaline as the stimulant. In the present study, we have compared the inhibitory activity of one of these compounds, Parthenolide, with that of crude feverfew extract. The effects of both on [14C]5-HT secretion from platelets and on platelet aggregation induced by a number of different stimulants were determined. The activating agents studied included the phorbol ester PMA, ADP, arachidonic acid, collagen, the thromboxane mimetic U46619, the calcium ionophore A23187, the diacylglycerol analogue OAG and adrenaline. The results show that there are marked similarities between the effects of feverfew extract and of Parthenolide on both [14C]5-HT secretion and platelet aggregation, which is consistent with the effects of feverfew extract on platelets being brought about by Parthenolide or similar compounds in the extract. Only in one case, when A23187 was used as the stimulatory agent, was there any discrepancy, which may have been due to materials in the extract other than Parthenolide. Both feverfew extract and Parthenolide were more effective as inhibitors of the [14C]5-HT secretion and aggregation induced by some agents and not others, and were most effective as inhibitors of the [14C]5-HT secretion (but not the aggregation) induced by PMA. This suggests that the effects of feverfew/Parthenolide on the protein kinase C pathway warrants further study.

Randomised double-blind placebo-controlled trial of feverfew in migraine prevention.[Pubmed:2899663]

Lancet. 1988 Jul 23;2(8604):189-92.

The use of feverfew (Tanacetum parthenium) for migraine prophylaxis was assessed in a randomised, double-blind, placebo-controlled crossover study. After a one-month single-blind placebo run-in, 72 volunteers were randomly allocated to receive either one capsule of dried feverfew leaves a day or matching placebo for four months and then transferred to the other treatment limb for a further four months. Frequency and severity of attacks were determined from diary cards which were issued every two months; efficacy of each treatment was also assessed by visual analogue scores. 60 patients completed the study and full information was available in 59. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks in each two-month period, and in the degree of vomiting; duration of individual attacks was unaltered. Visual analogue scores also indicated a significant improvement with feverfew. There were no serious side-effects.

Compounds extracted from feverfew that have anti-secretory activity contain an alpha-methylene butyrolactone unit.[Pubmed:2877077]

J Pharm Pharmacol. 1986 Sep;38(9):709-12.

Extracts of feverfew inhibit secretion of granular contents from platelets and neutrophils and this may be relevant to the therapeutic value of feverfew in migraine and other conditions. In this investigation we fractionated an extract of feverfew and obtained eleven fractions with antisecretory activity. The activity. The active fractions, together with two fractions that were devoid of anti-secretory activity, were examined using 1H NMR and infrared spectroscopy. All the active fractions (but neither of the inactive fractions) contained compounds with an alpha-methylene butyrolactone unit. Five compounds that contain this unit were identified as Parthenolide, 3-beta-hydroxyParthenolide, secotanapartholide A, canin and artecanin, all of which are sesquiterpene lactones. It is very likely that these and other sesquiterpene lactones that contain an alpha-methylene butyrolactone unit are responsible for the anti-secretory activity in extracts of feverfew.

Parthenolide is a sesquiterpene lactone found in the medicinal herb Feverfew. Parthenolide exhibits anti-inflammatory activity by inhibiting NF-κB activation; also inhibits HDAC1 protein without affecting other class I/II HDACs.

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