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Parthenolide is a substance found in several plants including feverfew and magnolia. Feverfew has been studied for its possible role in migraine headaches.

Parthenolide benefits and uses
Parthenolide may be helpful in cancer, leukemia and migraine headache. It also has anti-inflammatory and anti-tumor properties.

Naunyn Schmiedebergs Arch Pharmacol. 2016. Natural compounds for pediatric cancer treatment. This review will address the "status of the art" related to the potential of natural compounds that are undergoing investigation in combination with standard therapeutic protocols in preclinical and clinical studies and their importance for pediatric cancer treatment. The early studies of drug discovery of these natural compounds discussed here include the main targets, the cellular signaling pathways involved, and the potential modes of action. We also focus on some promising natural compounds that have shown excellent results in vitro and in vivo: Chebulagic acid, Apigenin, Norcantharidin, Saffron/Crocin, Parthenolide, Longikaurin E, Lupeol, Spongistatin 1, and Deoxy-variolin B.

Drug Discovery Today. 2013. Parthenolide: from plant shoots to cancer roots. Parthenolide, a sesquiterpene lactone (SL) originally purified from the shoots of feverfew (Tanacetum parthenium), has shown potent anticancer and anti-inflammatory activities. It is currently being tested in cancer clinical trials. Structure-activity relationship (SAR) studies of parthenolide revealed key chemical properties required for biological activities and epigenetic mechanisms, and led to the derivatization of an orally bioavailable analog, dimethylamino-parthenolide (DMAPT). Parthenolide is the first small molecule found to be selective against cancer stem cells (CSC), which it achieves by targeting specific signaling pathways and killing cancer from its roots.

Breast cancer, cervical cancer, skin cancer
Pharm Biol. 2015. Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines. Parthenolide (a sesquiterpene lactone), a bioactive compound of Tanacetum parthenium herb, has been reported for antioxidant and anticancer activities. 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. 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.

Melanoma anti cancer potential
Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro.
Melanoma Res. 2010. Lesiak K, Koprowska K, Zalesna I, Nejc D. Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
Metastatic melanoma is a highly life-threatening disease. The lack of response to radiotherapy and chemotherapy highlights the critical need for novel treatments. Parthenolide, an active component of feverfew Tanacetum parthenium, inhibits proliferation and kills various cancer cells mainly by inducing apoptosis. The aim of the study was to examine anticancer effects of parthenolide in melanoma cells in vitro. The cytotoxicity of parthenolide was tested in melanoma cell lines and melanocytes, as well as melanoma cells directly derived from a surgical excision. Adherent cell proliferation was measured by tetrazolium derivative reduction assay. Loss of the plasma membrane integrity, hypodiploid events, reactive oxygen species generation, mitochondrial membrane potential dissipation, and caspase-3 activity were assessed by flow cytometric analysis. Microscopy was used to observe morphological changes and cell detachment. Parthenolide reduced the number of viable adherent cells in melanoma cultures. Preincubation of parthenolide with the thiol nucleophile N-acetyl-cysteine protected melanoma cells from parthenolide-induced cell death suggesting the reaction with intracellular thiols as the mechanism responsible for parthenolide activity. In conclusion, the observed anticancer activity makes parthenolide an attractive drug candidate for further testing in melanoma therapy.

Leukemia
Parthenolide, a chemical derived from the feverfew plant, destroys acute myeloid leukemia (AML) cells, leaving normal bone marrow cells relatively unscathed. Moreover, the compound may get at the root of the disease because it also kills stem cells that give rise to AML. "This research is a very important step in setting the stage for future development of a new therapy for leukemia," senior author Dr. Craig T. Jordan, from the University of Rochester School of Medicine in New York, said in a statement. "We have proof that we can kill leukemia stem cells with this type of agent." The findings are based on lab dish experiments looking into parthenolide's destructive effects. The chemical showed a strong ability to trigger the death of human AML cells as well as chronic myelogenous leukemia (CML) cells. In fact, this agent was found to be much more specific to leukemia cells than the standard chemotherapy drug Ara-C. Further analysis revealed that parthenolide selectively targets stem cell populations. Thus, the investigators conclude that parthenolide is representative of "a potentially important new class of drugs for leukemia stem cell targeted therapy." Blood, online February 1, 2005.

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.
Blood. 2005.
Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSC) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide, a naturally-occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the NOD/SCID xenograft model, show that parthenolide also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug Ara-C, parthenolide is much more specific to leukemia cells. The molecular mechanism of parthenolide-mediated apoptosis is strongly associated with inhibition of NF-kappaB, pro-apoptotic activation of p53, and increased reactive oxygen species (ROS). Based on these findings, we propose that the activity of parthenolide triggers LSC specific apoptosis, and as such represents a potentially important new class of drugs for LSC targeted therapy.

Int J Oncol. 2010. Parthenolide treatment activates stress signaling proteins in high-risk acute lymphoblastic leukemia cells with chromosomal translocation t(4;11).

Research study
BMB Rep. 2013. Parthenolide inhibits osteoclast differentiation and bone resorbing activity by down-regulation of NFATc1 induction and c-Fos stability during RANKL-mediated osteoclastogenesis.

Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium.
Antimicrob Agents Chemother. 2005.
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 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.

Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer.
Invest New Drugs. 2004.
Feverfew is a botanical product that contains parthenolide. Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic activity. Feverfew has been used extensively without any formal pharmacokinetic analysis. A Phase I trial was conducted to evaluate the pharmacokinetics and toxicity of parthenolide given as a component of "feverfew." Feverfew (Tanacet trade mark ) was administered as a daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day was explored with subsequent dose escalations to 2, 3, and 4 mg. Assessment of plasma pharmacokinetics was performed on patients accrued to the trial. Solid phase extraction and mass spectroscopy were used to evaluate parthenolide plasma concentrations. The limit of detection for parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for response after every two cycles. hgFeverfew given on this schedule had no significant toxicity, and the maximum tolerated dose was not reached. When parthenolide was administered at doses up to 4 mg as a daily oral capsule in the feverfew preparation, there was not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed. CONCLUSION: Feverfew, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose-limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.

Microtubule-interfering activity of parthenolide.
Chem Biol Interact. 2004.
Parthenolide is an active sesquiterpene lactone present in a variety of medicinal herbs, well known as anti-inflammatory drug. It has recently been proposed as a chemotherapeutic drug, but the pharmacological pathways of its action have not yet been fully elucidated. Firstly, we explored whether the anticancer properties of parthenolide may be related to a tubulin/microtubule-interfering activity. We additionally compared bioactivities of parthenolide with those checked after combined treatments with paclitaxel in human breast cancer MCF-7 cells. Parthenolide exerted in vitro stimulatory activity on tubulin assembly, by inducing the formation of well-organized microtubule polymers. Light microscopy detections showed that parthenolide-induced alterations of either microtubule network and nuclear morphology happened only after combined exposures to paclitaxel. In addition, the growth of MCF-7 cells was significantly inhibited by parthenolide, which enhanced paclitaxel effectiveness. In conclusion, the antimicrotubular and antiproliferative effects of parthenolide, well known microtubule-stabilizing anticancer agent, may influence paclitaxel activity. The tubulin/microtubule system may represent a novel molecular target for parthenolide, to be utilized in developing new combinational anticancer strategies.

Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase.
Oncogene. 2004.
The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-kappaB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-kappaB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.

Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer.
Invest New Drugs. 2004.
Feverfew is a botanical product that contains parthenolide. Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic activity. Feverfew has been used extensively without any formal pharmacokinetic analysis. A Phase I trial was conducted to evaluate the pharmacokinetics and toxicity of parthenolide given as a component of "feverfew." Feverfew (Tanacet trade mark ) was administered as a daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day was explored with subsequent dose escalations to 2, 3, and 4 mg. Assessment of plasma pharmacokinetics was performed on patients accrued to the trial. Solid phase extraction and mass spectroscopy were used to evaluate parthenolide plasma concentrations. The limit of detection for parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for response after every two cycles. Feverfew given on this schedule had no significant toxicity, and the maximum tolerated dose was not reached. When parthenolide was administered at doses up to 4 mg as a daily oral capsule in the feverfew preparation, there was not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed. Feverfew, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose-limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.

Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms.
Carcinogenesis. 2004.
Data from our study for the first time confirm the anticancer property of parthenolide in an animal model, and provide evidence that the inhibitory effects on AP-1 and mitogen-activated protein kinases serve as one of the underlying mechanisms for the cancer chemopreventive property of parthenolide.

Depression effect of parthenolide in rodents
Depressant-like effects of parthenolide in a rodent behavioural antidepressant test battery.
J Pharm Pharmacol. 2008. Pandey DK, Rajkumar R, Mahesh R. Birla Institute of Technology & Science, Pilani, Rajasthan, India.
The anti-serotonergic effects of parthenolide demonstrated in platelets inspired the present psychopharmacological investigation, which employs a battery of rodent behavioural assays of depression. In mice, parthenolide (0.5-2 mg kg(-1)) exhibited dose-dependent depressant-like effects in a forced swim test and a tail suspension test, without affecting the baseline locomotor status. The doses (1 and 2 mg kg(-1)) that induced depressant-like effects were found to significantly reduce 5-hydroxytryptophan-induced head twitch response. Interaction studies revealed that the depressant-like effects of parthenolide (1 mg kg(-1)) were reversed more efficiently by serotonergic antidepressants (venlafaxine, escitalopram, citalopram, fluoxetine) than by others (desipramine, bupropion) tested. Chronic treatment of parthenolide (1 and 2 mg kg(-1)) augmented the hyper-emotionality of olfactory bulbectomized rats, when compared with sham rats, as observed in modified open field, elevated plus maze and social interaction paradigms. This study depicts the severe depressogenic potential of parthenolide (in its pure form) plausibly mediated by platelet/neuronal hypo-serotonergic effects.

Feverfew extract
Feverfew extract is sold by herb and raw ingredient suppliers as 0.2 percent parthenolide, to 0.4 percent, 0.5 percent, and 0.6 percent.

Questions
Q. My dad is fighting with acute myelogenous leukemia and he is in Iran. I came acroos your research about Parthenolide on the internet while I was desparatly searchin for any helpful type of treatment and I still am. He is under chemo now and he is 70 years old with the history of liver cirrhosis (non-viral or cancer). Could you please tell me if it's helping him to use Parthenolide? If yes,how we can find it? I live in US and maybe I can send it for them. I realy appreciate your advise and help.
     A. We don't know of any source that sells parthenolide by itself, but the herb feverfew has parthenolide in it. We cannot predict the response of parthenolide or feverfew to AML, there have not been much human studies.