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by Ray Sahelian, M.D.
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.
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.
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