Feverfew

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 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;4:587-94).

In 2010, Tanaka et al. found that the NF-kappaB inhibitors parthenolide and magnolol can effectively block NF-kappaB–mediated gene expression, as well as UVB-induced proliferation of keratinocytes and melanocytes in murine skin, suggesting that both compounds may play a role in preventing photoaging (Curr. Drug Metab. 2010;11:431-5).

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 with untreated animals or those treated with either agent alone. The combination was also linked to diminished lung metastases. Animals that were 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;4:1004-12).

Recently, investigators studied the anticancer effects of parthenolide in melanoma cells in vitro, in melanoma cell lines and melanocytes, and in melanoma cells obtained from a surgical excision, finding that the herbal compound decreased the number of viable adherent cells in melanoma cultures. The researchers also noted that preincubation of parthenolide with the thiol nucleophile N-acetylcysteine shielded melanoma cells from parthenolide-induced cell death, implying that the mechanism attributable to parthenolide activity is the reaction with intracellular thiols. They concluded that the apparent anticancer activity of parthenolide warrants further evaluation for melanoma therapy (Melanoma Res. 2010;20:21-34).

Problems with Parthenolide and Parthenolide-Free Feverfew

The Compositae family is known to cause contact dermatitis in susceptible individuals, and Compositae allergy is among the top 10 contact sensitivities in Europe. Sesquiterpene lactones are considered to be the primary sensitizers (Med. Pregl. 2003;56:43-9). Indeed, parthenolide has become known as a potent skin sensitizer (Inflammopharmacology 2009;17:42-9). When feverfew is ingested orally for migraines, oral ulcers have been reported. Feverfew has many benefits that are not derived from parthenolide. Researchers found that a form of feverfew had the parthenolide portion removed, and therefore could be used more safely as a topical ingredient.

In 2008, Martin et al. established the in vitro and in vivo antioxidant efficacy of a parthenolide-depleted feverfew extract. Shown to exhibit greater activity than vitamin C, the extract restored cigarette smoke–mediated depletion of cellular thiols, diminished the formation of UV-induced hydrogen peroxide, and inhibited proinflammatory cytokine release in vitro. In addition, the topical formulation decreased UV-induced epidermal hyperplasia, DNA damage, and apoptosis in vivo. Finally, a clinical study of the extract revealed that treatment significantly reduced UV-induced erythema vs. placebo 24 hours after exposure. Consequently, the researchers expressed confidence in their parthenolide-depleted feverfew formulation to protect the skin from exogenous oxidizing influences (Arch. Dermatol. Res. 2008;300:69-80).

In 2009, some of the same investigators assessed the anti-inflammatory capacity of the parthenolide-depleted feverfew extract that they developed. In vitro, the extract hindered the activity of several proinflammatory enzymes (that is, 5-lipoxygenase, phosphodiesterase-3, and phosphodiesterase-4), as well as the release of proinflammatory mediators. In vivo, the extract thwarted oxazolone-induced dermatitis and was more effective than regular feverfew in treating TPA (12-O-tetradecanoylphorbol 13-acetate)–induced dermatitis. In a clinical assessment, the investigators found that their extract diminished erythema in a methyl nicotinate-induced vasodilation model. They concluded that the parthenolide-depleted feverfew extract exhibits strong anti-inflammatory activity but without the accompanying sensitizing activity characteristic of whole feverfew (Inflammopharmacology 2009;17:42-9).

Some sensitivity to these agents may still arise, however. In 2010, Paulsen et al. investigated the tolerance of individuals with contact allergy to feverfew using patch tests with new parthenolide-depleted feverfew formulations in a small study with seven patients. Subjects were patch tested with two parthenolide-depleted creams. The researchers noted that four patients tested positive to one of the agents, and reactivity was linked to simultaneous positive response to parthenolide. Two years later, they analyzed this cream, finding no parthenolide, which they ascribed to degradation of the compound (Contact Dermatitis 2010;63:146-50).