DNC NEWS: Feverfew, Stem cells and the treatment of Cancer
June 29, 2005
Subject: Research on the common herb feverfew suggests it may play an important role in the treatment of Cancer.
Feverfew is the common name for the herb Tanacetum parthenium , a member of the Chrysanthemum family, often called bachelor buttons. Traditionally, as the name implies, it was used for lowering fevers. More recently we have seen it promoted for its anti-inflammatory action because it inhibits inflammatory prostaglandins, leukotrienes and thromboxanes. It is probably best known though for preventing migraine headaches.
The main active chemical in Feverfew is called parthenolide. It is something of a tricky ingredient. The amount in plants varies considerably. Concentrating it can be difficult as it is easily destroyed in processing. The amount found in herbal preparations sold over the counter is hard to predict: some have none. Twenty years ago, when we were in Naturopathic Medical School , the rule was to encourage migraine patients to grow fresh Feverfew in their garden or windowsill and to eat a leaf a day. This was a more dependable source and reliable treatment than the store bought pills. These days the professional lines of herbal extracts do offer carefully standardized extracts that contain about 1 mg of pure parthenolide per capsule.
A rapidly growing body of research suggests parthenolide may play a valuable and intriguing role in treating cancer. This month Monica Guzman and her colleagues published a paper in Blood on the effect of parthenolide on chronic myologenous leukemia (CML). [i] According to their work parthenolide is the only chemical found which kills leukemia stem cells. .
The study of cancer stem cells is relatively new although theories that such cells might exist go back a hundred years. According to our current understanding, cancer stem cells occur in blood cancer, brain and breast cancers. Probably other cancers as well. Contrary to what is generally thought, not all tumor cells cause metastatic cancer. In experimental breast tumors only a tiny fraction - less than one percent - of tumor cells are actually capable of causing metastasis. These highly malignant cells are now called stem cells. I often use the analogy of juvenile delinquent kids in gangs. Relatively good kids can do dumb things when under the influence of really bad kids. It seems to be this way with cancer as well. A few genuinely bad cells will influence their cohorts to cause trouble.
These tumor stem cells were first identified in leukemia. [ii] When the idea that stem cells occurred in other types of cancer, notably breast cancer, was first announced in 2003 this was considered big news: the idea was so startling it was considered a, “Paradigm shift in cancer research.”
The existence of these highly nasty few cells may explain why current treatments for metastatic breast cancer often fail. Max S. Wicha, MD, an oncologist and director of the University of Michigan Comprehensive Cancer Center, as quoted in a 2003 press release.
"The goal of all our existing therapies has been to kill as many cells within the tumor as possible," said Wicha. But this study "suggests that the current model may not be getting us anywhere, because we have been targeting the wrong cells with the wrong treatments."
According to Michael F. Clarke, MD, a professor of internal medicine, who directed the breast cancer stem cell study, "As few as 100 to 200 of these tumor-inducing cells, isolated from eight of nine tumors in the study, easily induced tumors in mice, while tens of thousands of the other cancer cells from the original tumor failed to do so.”
In the light of this information we start to understand that the strategies that aim only at shrinking tumors with radiation or chemotherapy are doomed. These therapies are based on a wrong understanding of cancer; size alone is not critical. What is important is killing these active cancer stem cells.
If parthenolide can kill cancer stem cells, we should stop and pay attention. This isn't the first study suggesting that parthenolide has an effect on cancer. A study from this past April suggests that parthenolide can inhibit growth of pancreatic cancer cells. [iii] A study published last October says parthenolide inhibited the growth of breast cancer cells an increased the effectiveness of the chemotherapy drug paclitaxel. [iv] In a paper published this week, Feverfew was given to rats with breast cancer. The feverfew slowed tumor growth and increased the effectiveness of the chemotherapy drug Docetaxel at killing the cancer cells, preventing metastasis and increasing survival time. [v]
A number of papers have come out attempting to explain why Feverfew kills cancer cells. One from last November suggests that it suppressed NF-kappaB and sustained JNK. [vi] The study that I find most interesting was published a year ago in May, 2004 by researchers in Singapore . They looked at Feverfew's effect on the biochemistry of colon cancer cells and their research suggests a mechanism of action very parallel to that seen in vitamin K-3 and vitamin C. Recall that a combination of Vitamin K-3 and Vitamin C induces a unique form of cancer cell death called autoschizis. Like vitamin K-3, Feverfew appears to deplete glutathione in the cancer cells and causes cell death while leaving healthy cells unaffected. [vii] Also like vitamin K-3, the effect of Feverfew on cancer cells is stopped by N-acetyl-cysteine (NAC) a nutritional supplement that increases glutathione levels. In autoschizis, the cells don't die via traditional apoptosis; instead, the cell membrane appears to be slashed open and the cell contents leak out. A paper from July, 2003 watching the effect of feverfew on leukemia cells describes their cell death as atypical apoptosis. [viii] The description sounds remarkably similar to what the Vitamin K researchers describe
This would suggest three things to me. First, Feverfew may potentiate the effect of using vitamin K-3 and vitamin C. Second patients using Feverfew should not take N-acetyl-cysteine or over emphasize supplements which increase glutathione levels. Third, the various cancer treatments which promote high levels of glutathione may not be as useful as we once thought.
Feverfew appears safe for cancer patients to take. In August, 2004 a Phase I dose escalation trial using Feverfew in cancer patients was published and reported no adverse effects at doses up to 4 mg of parthenolide a day. [ix] Various papers have theorized that Feverfew may have an anticoagulant effect and should be used with caution during surgery and might interact with other drugs.
Our clinical experience has been that Feverfew is well tolerated and that adverse reactions are extremely rare.
Feverfew looks good from a number of angles. It is the only chemical found that kills leukemia cancer stem cells. Research suggests it may play a similar role in other cancers. The mechanisms proposed so far for its action suggest it will be effective for many different cancers. It potentiates the effects of several chemotherapy drugs and will likely help with others. It appears to be safe and well tolerated, not injuring healthy non-cancerous cells.
[i] Blood. 2005 Jun 1;105(11):4163-9
The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells .
Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR , Howard DS, Jordan CT.
University of Rochester School of Medicine, 601 Elmwood Ave, Box 703, Rochester, NY 14642, USA. email@example.com
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 (LSCs) 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 (PTL), 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 nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappaB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
PMID: 15687234 [PubMed - in process]
[ii] Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16220-5. Epub 2002 Nov 25.
Preferential induction of apoptosis for primary human leukemic stem cells.
Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ , Jordan CT.
Blood and Marrow Transplant Program, Markey Cancer Center, Division of HematologyOncology, University of Kentucky Medical Center, Lexington, KY 40536-0093 USA.
Acute myelogenous leukemia (AML) is typically a disease of stem progenitor cell origin. Interestingly, the leukemic stem cell (LSC) shares many characteristics with normal hematopoietic stem cells (HSCs) including the ability to self-renew and a predominantly G(0) cell-cycle status. Thus, although conventional chemotherapy regimens often ablate actively cycling leukemic blast cells, the primitive LSC population is likely to be drug-resistant. Moreover, given the quiescent nature of LSCs, current drugs may not effectively distinguish between malignant stem cells and normal HSCs. Nonetheless, based on recent studies of LSC molecular biology, we hypothesized that certain unique properties of leukemic cells could be exploited to induce apoptosis in the LSC population while sparing normal stem cells. In this report we describe a strategy using treatment of primary AML cells with the proteasome inhibitor carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal (MG-132) and the anthracycline idarubicin. Comparison of normal and leukemic specimens using in vitro culture and in vivo xenotransplantation assays shows that the combination of these two agents induces rapid and extensive apoptosis of the LSC population while leaving normal HSCs viable. Molecular genetic studies using a dominant-negative allele of inhibitor of nuclear factor kappaB (IkappaBalpha) demonstrate that inhibition of nuclear factor kappaB (NF-kappaB) contributes to apoptosis induction. In addition, gene-expression analyses suggest that activation of p53-regulated genes are also involved in LSC apoptosis. Collectively, these findings demonstrate that malignant stem cells can be preferentially targeted for ablation. Further, the data begin to elucidate the molecular mechanisms that underlie LSC-specific apoptosis and suggest new directions for AML therapy.
PMID: 12451177 [PubMed - indexed for MEDLINE]
[iii] Mol Cancer Ther. 2005 Apr;4(4):587-94.
Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells.
Yip-Schneider MT, Nakshatri H, Sweeney CJ, Marshall MS, Wiebke EA, Schmidt CM.
Department of Surgery, Indiana University School of Medicine, Room 041, Building R4, 1044 West Walnut Street, Indianapolis , IN 46202 , USA . firstname.lastname@example.org <email@example.com>
Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-kappa B inhibitor, parthenolide, a sesquiterpene lactone isolated from the herb feverfew, in three human pancreatic tumor cell lines (BxPC-3, PANC-1, and MIA PaCa-2). Parthenolide inhibited pancreatic cancer cell growth in a dose-dependent manner with substantial growth inhibition observed between 5 and 10 micromol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-kappa B inhibitory protein, I kappa B-alpha, and decreased NF-kappa B DNA binding activity. We have previously shown that nonsteroidal anti-inflammatory drugs (NSAID) suppress the growth of pancreatic cancer cells. To determine whether inhibition of the NF-kappa B pathway by parthenolide could sensitize pancreatic cancer cells to NSAID inhibition, BxPC-3, PANC-1, and MIA PaCa-2 cells were treated with parthenolide and the NSAID sulindac, either alone or in combination. Treatment with the combination of parthenolide and sulindac inhibited cell growth synergistically in MIA PaCa-2 and BxPC-3 cells and additively in PANC-1 cells. In addition, treatment with the parthenolide/sulindac combination lowered the threshold for apoptosis. Increased levels of I kappa B-alpha protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-kappa B DNA binding and transcriptional activities were detected in cells treated with the combination compared with the single agents, demonstrating cooperative targeting of the NF-kappa B pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-kappa B inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma.
PMID: 15827332 [PubMed - in process]
[iv] Chem Biol Interact. 2004 Oct 15;149(2-3):165-73.
Microtubule-interfering activity of parthenolide.
Miglietta A, Bozzo F, Gabriel L, Bocca C.
Department of Experimental Medicine and Oncology, University of Torino , Corso Raffaello 30, 10125 Torino , Italy . firstname.lastname@example.org
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.
PMID: 15501437 [PubMed - indexed for MEDLINE]
[v] Mol Cancer Ther. 2005 Jun;4(6):1004-12.
The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer.
Sweeney CJ, Mehrotra S, Sadaria MR, Kumar S, Shortle NH, Roman Y, Sheridan C, Campbell RA, Murry DJ, Badve S, Nakshatri H.
Department of Medicine, Indiana University School of Medicine, Indianapolis , USA .
Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor kappaB (NF-kappaB) and activation of the c-Jun NH(2)-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45beta1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-kappaB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-kappaB.
PMID: 15956258 [PubMed - in process]
[vi] Carcinogenesis. 2004 Nov;25(11):2191-9. Epub 2004 Jul 15.
Suppressed NF-kappaB and sustained JNK activation contribute to the sensitization effect of parthenolide to TNF-alpha-induced apoptosis in human cancer cells.
Zhang S, Lin ZN, Yang CF, Shi X, Ong CN, Shen HM.
Department of Community, Occupational and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Parthenolide (PN) is the main sesquiterpene lactone found in feverfew with potent anti-inflammatory function. The anticancer property of PN has been demonstrated in both in vitro cell culture and in vivo animal model, while the molecular mechanisms remain to be further elucidated. In the present study, we evaluated the involvement of nuclear transcription factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) in the anticancer activity of PN by examining the sensitization effect of PN on tumor necrosis factor (TNF)-alpha-induced apoptosis in human cancer cells. Pre-treatment with PN greatly sensitized various human cancer cells to TNF-alpha-induced apoptosis. Such sensitization is closely associated with the inhibitory effect of PN on TNF-alpha-mediated NF-kappaB activation. Our study revealed a new mechanism that PN inhibits TNF-alpha-mediated NF-kappaB activation via disrupting the recruitment of the IkappaB kinases (IKK) complex to TNF receptor, which then blocked the subsequent signaling events including IKK kinase activation, IkappaBalpha degradation, p65 nuclear translocation, DNA binding and transactivation. Moreover, PN also markedly enhanced and sustained TNF-alpha-mediated JNK activation. A specific JNK inhibitor (SP600125), as well as over-expression of dominant-negative forms of JNK1 and JNK2 abolished the sensitization effect of PN on TNF-alpha-induced apoptosis. It is thus believed that suppressed NF-kappaB activation and sustained JNK activation contribute to the sensitization effect of PN to TNF-alpha-mediated cell death in human cancer cells.
PMID: 15256485 [PubMed - in process]
[vii] Cancer Lett. 2004 May 28;208(2):143-53.
Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells.
Zhang S, Ong CN, Shen HM.
Department of Community, Occupational and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore 117597.
Parthenolide is one of the main components responsible for the anti-inflammatory property of Feverfew. Recently, parthenolide has shown to induce apoptosis in cancer cells. Here we further studied the mechanism of parthenolide-induced apoptosis by focusing on the role of intracellular thiols and calcium in a human colorectal cancer cell, COLO 205. Parthenolide rapidly depleted intracellular thiols, including both free glutathione (GSH) and protein thiols. Concomitantly, there were dose- and time-dependent increases in intracellular reactive oxygen species (ROS) and calcium levels. Increased expression of GRP78 protein, a marker for endoplasmic reticulum stress was also detected. All these changes preceded parthenolide-induced apoptotic cell death. More importantly, pretreatment with N-acetylcysteine, a precursor of GSH synthesis, protected the cells from parthenolide-induced thiol depletion, ROS production, cytosolic calcium increase and completely blocked parthenolide-induced apoptosis. On the contrary, pretreatment of buthionine sulfoximine, an inhibitor of GSH synthesis sensitized the cell to apoptosis. These data clearly demonstrate that the intracellular thiols and calcium equilibrium play a critical role in parthenolide-induced apoptotic cell death.
PMID: 15142672 [PubMed - indexed for MEDLINE]
[viii] Cell Cycle. 2003 Jul-Aug;2(4):377-83
Cell cycle effects and caspase-dependent and independent death of HL-60 and Jurkat cells treated with the inhibitor of NF-kappaB parthenolide.
Pozarowski P, Halicka DH, Darzynkiewicz Z.
Brander Cancer Research Institute, New York Medical College , Valhalla , New York , USA .
The sesquiterpene parthenolide (PRT) is an active component of Mexican-Indian medicinal plants and also of the common herb of European origin feverfew. PRT is considered to be a specific inhibitor of NF-kappaB. Human leukemic HL-60, Jurkat, and Jurkat IkappaBalphaM cells, the latter expressing a dominant-negative IkappaBalpha and thus having non-functional NF-kappaB, were treated with PRT and activation of caspases, plasma membrane integrity, DNA fragmentation, chromatin condensation (probed by DNA susceptibility to denaturation), and changes in cell morphology were determined. As a positive control for apoptosis cells were treated with topotecan (TPT) and H2O2. At 2-8 microM concentration PRT induced transient cell arrest in G2 and M followed by apoptosis. A narrow range of PRT concentration (2-10 microM) spanned its cytostatic effect, induction of apoptosis and induction of necrosis. In fact, necrotic cells were often seen concurrently with apoptotic cells at the same PRT concentration. Atypical apoptosis was characterized by loss of plasma membrane integrity very shortly after caspases activation. In contrast, a prolonged phase of caspase activation with preserved integrity of plasma membrane was seen during apoptosis induced by TPT or H2O2. Necrosis induced by PRT was also atypical, characterized by rapid rupture of plasma membrane and no increase in DNA susceptibility to denaturation. Using Jurkat cells with inactive NF-kappaB we demonstrate that cell cycle arrest and the mode of cell death induced by PRT were not caused by inhibition of NF-kappaB. The data suggest that regardless of caspase activation PRT targets plasma membrane causing its destruction. A caution, therefore, should be exercised in interpreting data of the experiments in which PRT is used with the intention to specifically prevent activation of NF-kappaB.
PMID: 12851492 [PubMed - indexed for MEDLINE]
[ix] Invest New Drugs. 2004 Aug;22(3):299-305.
Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer.
Curry EA 3rd, Murry DJ, Yoder C, Fife K, Armstrong V, Nakshatri H, O'Connell M, Sweeney CJ.
Department of Pharmacy Practice, Purdue University , Indianapolis , IN , USA .
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.