Sign up to a FREE Supplement Research Update newsletter. Twice a month we email a brief abstract of several studies on various supplements and natural medicine topics and their practical interpretation by Ray Sahelian, M.D. We will mention parthenolide research as it becomes available.

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

Parthenolide potential benefits
Parthenolide may be helpful in leukemia and migraine headache. Parthenolide also has anti-inflammatory and anti-tumor properties.

Parthenolide Research Update
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." SOURCE: Blood, online February 1, 2005.

The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.
Blood. 2005 Feb 1.
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.

Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium.
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 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.

Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer.
Invest New Drugs. 2004 Aug;22(3):299-305.
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. RESULTS: 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. 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 Oct 15;149(2-3):165-73.
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.

Anti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear's foot.
Pharmacol Biochem Behav. 2004 Oct;79(2):299-302.
Sesquiterpene lactones possess a variety of biological activities, including anti-inflammatory activity. Two plants native to the southeastern United States, Magnolia grandiflora (L.) and Smallanthus uvedalius (L.) [syn Polymnia uvedalius (L.)], are novel sources of the sesquiterpene lactones parthenolide and enhydrin, respectively. In this study, the anti-inflammatory and anti-hyperalgesic effects of these isolated lactones from these two plant sources were evaluated in the rat carrageenan inflammation model. These findings suggest that parthenolide and enhydrin from these plant sources may be useful in the treatment of inflammatory pain.

Sesquiterpene lactone parthenolide blocks lipopolysaccharide-induced osteolysis through the suppression of NF-kappaB activity.
J Bone Miner Res. 2004 Nov;19(11):1905-16.
Effective treatment for bacteria-induced bone lytic diseases is not yet available. In this study, we showed that parthenolide, an NF-kappaB inhibitor found in medicinal herbs, can block LPS-induced osteolysis. Parthenolide does this by inhibiting osteoclastogenesis and bone resorption and promoting apoptosis of osteoclasts through the suppression of NF-kappaB activity. INTRODUCTION: Osteolysis induced by chronic gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we investigated the effect of parthenolide on LPS-induced osteolysis in vivo and studied its role in osteoclastogenesis, bone resorption, apoptosis, and NF-kappaB activity. CONCLUSION: The NF-kappaB pathway is known to mediate both osteoclast differentiation and survival. These findings indicate that parthenolide blocks LPS-induced osteolysis through the suppression of NF-kappaB activity and suggest that it might have therapeutic value in bacteria-induced bone destruction.

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 Sep 23;23(44):7330-44.
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 but not Smac/DIABLO 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 Aug;22(3):299-305.
PURPOSE: 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." PATIENTS AND METHODS: 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. RESULTS: 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. 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.

Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms.
Carcinogenesis. 2004 Aug;25(8):1449-58.
Parthenolide is a major sesquiterpene lactone of feverfew (Tanacetum parthanium) with known anti-inflammatory activity. However, the anticancer effects of parthenolide have not been well studied. In the present investigation, we examined the cancer chemopreventive property of parthenolide using a combination of in vivo and in vitro approaches. We first tested the anticancer effect of parthenolide in UVB-induced skin cancer model. Mice fed with parthenolide (1 mg/day) showed a delayed onset of papilloma incidence, a significant reduction in papilloma multiplicity (papilloma/mouse) and sizes when compared with the UVB-only group. To our surprise, neither parthenolide nor the known cyclooxygenase (COX)-2 inhibitor celecoxib inhibit UVB-induced COX-2 expression and epidermal prostaglandin E2 (PGE2) production. We next investigated the molecular mechanism(s) involved in its anticancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic concentrations of parthenolide significantly inhibited UVB-induced activator protein-1 DNA binding and transcriptional activity. In addition, parthenolide pre-treatment also inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More importantly, we found that impaired AP-1, JNK and p38 signaling led to the sensitization of JB6 cells to UVB-induced apoptosis. 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.

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

Parthenolide 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.