Cosmeceutical Critique: Feverfew / Parthenolide
Dr. Leslie Baumann
Tanacetum parthenium, also known as feverfew, is a perennial herb with a long history of traditional use (Principles and Practice of Phytotherapy. Churchill Livingstone: London, UK. 2000;385-93). Evidence of the anti-inflammatory properties of feverfew and, specifically, its major sesquiterpene lactone, parthenolide, have been accruing over the last few decades and are now considered well established (Carcinogenesis. 2004;25(8):1449-58). Parthenolide is obtained as a hydroalcoholic extract of aerial parts of the plant (Antimicrob Agents Chemother. 2005;49(1):176-82) and is known to inhibit nuclear factor-kappaB (NF-kappaB) and exhibit antiproliferative properties (Biochem Biophys Res Commun. 2005;332(2):321-5). Feverfew also contains the potent antioxidant melatonin (Lancet. 1997;350(9001):1598-9).
In a Medline literature review of herbal agents that many people take but that might warrant discontinuing before dermatologic surgery, authors cited feverfew for its known success as a treatment for migraines (BMJ. 1985;291:569-73) and arthritis as well as its ant-inflammatory activity in blocking phospholipase breakdown of arachidonic acid into prostaglandins and leukotrienes (Dermatol Surg. 2001;27(8):759-63; Biochem Pharmacol. 1992;43:2313-20; Prostaglandins Leukot Med. 1982;8:653-60). They noted that platelet aggregation is also induced by the feverfew extract parthenolide and a byproduct of the arachidonic acid cascade, thromboxane A2 (Dermatol Surg. 2001;27(8):759-63; J Pharm Pharmacol. 1987;39:459-65; J Pharm Pharmacol. 1990;42:553-7).
When considering the potential effects of parthenolide on various cancer cells, it is important to note that activation of the transcription factor NF-kappaB is often involved (Mol Cancer Ther. 2005;4(4):587-94; Cancer Res. 2005;65(7):2804-14; Biochem Biophys Res Commun. 2005;332(2):321-5; Mol Cancer Ther. 2005;4(6):1004-12). In fact, through a series of studies during the last several years, parthenolide has become known as an NF-kappa B inhibitor.
Parthenolide has been consistently shown to exhibit in vitro antitumor activity (Mol Cancer Ther. 2005;4(6):1004-12). A recent in vitro and in vivo investigation of the cancer chemopreventive potential of parthenolide using the UVB-induced skin cancer model revealed that SKH-1 hairless mice given parthenolide exhibited later onset of papilloma, significantly fewer papillomas/mouse and smaller lesions in comparison to mice exposed only to UVB but not fed the primary component of feverfew. The in vitro phase of the study, using cultured JB6 murine epidermal cells, showed that non-cytotoxic concentrations of parthenolide pre-treatment significantly suppressed UVB-induced activator protein-1 DNA binding and transcriptional activity as well as c-Jun-N-terminal kinase (JNK) and p38 kinase signaling activation, all of which might be crucial in the anticancer mechanism of action of parthenolide, according to the authors (Carcinogenesis. 2004;25(8):1449-58). In a study conducted by three of the same investigators, parthenolide was found to sensitize UVB-induced apoptosis through pathways that depend on protein kinase C (Carcinogenesis. 2005 Jul 28; [Epub ahead of print]).
In another recent study, investigators found that parthenolide effectively blocked the gene expression mediated by NF-kappaB and the production of basic fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1) as well as the UVB-induced proliferation of keratinocytes and melanocytes in mouse skin, prompting the conclusion that inhibitors of NF-kappaB, particularly parthenolide, have potential to prevent cutaneous photoaging (J Pharmacol Exp Ther. 2005 Jul 18; [Epub ahead of print]).
In addition to its potential activity against skin cancer and photoaging, the primary component of feverfew confers other benefits pertinent to dermatology. Researchers recently identified potent intracellular antioxidant activity displayed by parthenolide in hippocampal HT22 cells, properties that are mediated by an increase of glutathione but not found to mediate the sesquiterpene lactone’s antiproliferative activities or its suppression of NF-kappaB (Biochem Biophys Res Commun. 2005;332(2):321-5). Parthenolide has also shown marked leishmanicidal activities suitable enough, according to investigators, to be considered for inclusion in the development of new drugs to treat this disease (Antimicrob Agents Chemother. 2005;49(1):176-82). While several in vitro studies have indicated that parthenolide confers anti-inflammatory effects, a recent in vivo study with mice demonstrated that the sesquiterpene lactone component of feverfew modestly suppressed only one gene, interleukin (IL)-6 after lipopolysaccharide-induced increases (J Inflamm (Lond). 2005 Jun 29;2:6). The authors concluded that more study of the effects of parthenolide and other herbal constituents on inflammatory gene expression using animal models is needed to assess the efficacy of various supplements (J Inflamm (Lond). 2005 Jun 29;2:6).
A recent finding regarding the primary constituent of feverfew indicates the expanding breadth and depth of the potential medical applications of this herbal extract. Parthenolide was recently found to exhibit significant activity in suppressing hepatitis C virus (HCV), which is often a precursor to cirrhosis and hepatocellular carcinoma (Bioorg Med Chem. 2005 Sep 1; [Epub ahead of print]). In addition, parthenolide has also been found to enhance in hepatoma cells the apoptosis induced by fenretinide (N-4-hydroxyphenyl retinamide, 4HPR), a synthetic anticancer retinoid and established apoptosis-inducing agent. In a study focusing on the relationship of these two compounds, parthenolide was found to up- or down-regulate 35 apoptosis-related genes and its role as an adjuvant anticancer agent against hepatoma was elucidated (Cancer Res. 2005;65(7):2804-14).
Parthenolide has demonstrated potential activity against several other cancer types. The herbal compound has been found to preferentially induce apoptosis in acute myelogenous leukemia stem cells without adversely affecting normal blood cells (Expert Opin Biol Ther. 2005;5(9):1147-52). In addition, in a recent study, parthenolide dose-dependently induced apoptosis in all four cholangiocarcinoma cell lines with sarcomatous SCK cells more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Investigation of the greater susceptibility of SCK cells to parthenolide revealed Bcl-2 family molecular involvement and indicated that impaired expression of Bcl-X(L) might play a role in the greater sensitivity of SCK cells, as compared to other adenomatous cholangiocarcinoma cells, to parthenolide (Cancer Res. 2005;65(14):6312-20).
In a study of the effects of parthenolide in three human pancreatic tumor cell lines (BxPC-3, PANC-1, and MIA PaCa-2), the sesquiterpene lactone dose-dependently inhibited cancer cell growth in all three lines as well as the level of NF-kappaB inhibitory protein I kappa B-alpha, and reduced NF-kappaB DNA binding activity. Investigators also found that combining parthenolide treatment of cells with the nonsteroidal anti-inflammatory drug (NSAID) sulindac synergistically suppressed cell growth in MIA PaCa-2 and BxPC-3 cells and cumulatively in PANC-1 cells and reduced the apoptosis threshold. The combined treatment also increased I kappa B-alpha levels and decreased NF-kappaB DNA binding and transcriptional activities more than the compounds alone. The researchers concluded that parthenolide is a viable NF-kappaB inhibitor to be used in combination with an NSAID to treat pancreatic adenocarcinoma (Mol Cancer Ther. 2005;4(4):587-94).
Parthenolide has also been demonstrated in an in vitro MDA-MB-231 cell-derived xenograft metastasis model of breast cancer to be effective alone or combined with docetaxel in decreasing colony formation, as well as inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45beta1. Combining the treatments also enhanced survival for animal subjects compared to untreated animals or those treated with either agent alone, and was linked to diminished lung metastases. Animals treated with either or both agents were found to have lower NF-kappaB levels in residual tumors and lung metastases. Investigators suggest that these findings are the first to show that parthenolide exhibits significant in vivo chemosensitizing activity in a metastatic breast cancer environment (Mol Cancer Ther. 2005;4(6):1004-12).
Feverfew is a member of the Compositae family, which is known to cause contact dermatitis in susceptible individuals, and Compositae allergy is among the top ten contact sensitivities in Europe. Sesquiterpene lactones are considered to be the primary sensitizers (Med Pregl. 2003;56(1-2):43-9). Nevertheless, adverse reactions to feverfew are considered to be minimal and rare.
Feverfew is best known as an effective herbal alternative for treating migraine headaches. New evidence is emerging that numerous other health benefits might be derived from this plant and particularly its chief component parthenolide. The findings regarding anticarcinogenic and anti-inflammatory capacity are promising and may soon have dermatologic implications. Formulations must be developed to account for the allergenic potential of parthenolide while still harnessing its potency. While much more research is necessary, this herbal product appears to be poised for cutaneous applications.
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