Feverfew

Feverfew, a member of the Asteraceae or Compositae family, is a perennial herb with a long history of traditional use.

The expression "feverfew" is derived from the Latin for fever reducer. Evidence of the anti-inflammatory properties of feverfew has been accruing over the last several decades and is now considered well established (Carcinogenesis 2004;25:1449-58).

Photo (c)Courtesy Wikimedia Commons/Dr Paul G Tuli/Creative Commons License

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 (Br. Med. J. [Clin. Res. Ed.] 1985;291:569-73). In addition, feverfew is known for success in treatment for arthritis, as well as its anti-inflammatory activity in blocking phospholipase breakdown of arachidonic acid into prostaglandins and leukotrienes (Dermatol. Surg. 2001;27:759-63; 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 A (Dermatol. Surg. 2001;27:759-63; J. Pharm. Pharmacol. 1990;42:553-7; J. Pharm. Pharmacol. 1987;39:459-65). Parthenolide is obtained as a hydroalcoholic extract of aerial parts of the plant, and is known to inhibit nuclear factor–kappaB (NF-kappaB) and to exhibit antiproliferative properties (Biochem. Biophys. Res. Commun. 2005;332:321-5). Feverfew also contains the potent antioxidant melatonin (Lancet 1997;350:1598-9).

Parthenolide Potency

Parthenolide has been consistently shown to exhibit in vitro antitumor activity (Mol. Cancer Ther. 2005;4:1004-12). 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 that were given parthenolide exhibited later onset of papillomas and significantly fewer papillomas in comparison to mice that were exposed only to UVB but not fed the primary component of feverfew. The in vitro phase of the study, which used cultured JB6 murine epidermal cells, showed that noncytotoxic concentrations of parthenolide pretreatment significantly suppressed UVB-induced activator protein-1 DNA binding and transcriptional activity, as well as JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase signaling activation, all of which might be crucial in the anticancer mechanism of action of parthenolide, according to the authors (Carcinogenesis 2004;25:1449-58). 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;26:2149-56).

In another recent study, investigators found that parthenolide effectively blocked the gene expression mediated by NF-kappaB and the production of bFGF (basic fibroblast growth factor) and MMP-1 (matrix metalloprotease-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;315:624-30).

In addition to its potential activity against skin cancer and photoaging, the feverfew constituent parthenolide 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;332:321-5).

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;49:176-82).

Although several in vitro studies have indicated that parthenolide imparts anti-inflammatory effects, a recent in vivo study with mice demonstrated that the sesquiterpene lactone component of feverfew modestly suppressed only one gene, interleukin-6 after lipopolysaccharide-induced increases (J. Inflamm. (Lond). 2005;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.

A recent finding regarding parthenolide 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, which is often a precursor to cirrhosis and hepatocellular carcinoma (J. Inflamm. [Lond]. 2005;2:6). In hepatoma cells, parthenolide has been found to enhance the apoptosis induced by fenretinide (N-4-hydroxyphenyl retinamide, or 4-HPR), a synthetic anticancer retinoid and an established apoptosis-inducing agent. In a study focusing on the relationship of these two compounds, parthenolide was found to upregulate or downregulate 35 apoptosis-related genes, and its role as an adjuvant anticancer agent against hepatoma was elucidated (Cancer Res. 2005;65:2804-14).

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;5:1147-52). 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, compared with other adenomatous cholangiocarcinoma cells, to parthenolide (Cancer Res. 2005;65:6312-20).

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 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).

Conclusion

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. Recent success has been observed with parthenolide-depleted feverfew. The ability to take a naturally occurring ingredient and improve it by removing an undesirable part of the chemical structure is the future of "natural" skin care, in my opinion. Will we be seeing more of the tweaked ingredients? I believe we will.

Feverfew, a member of the Asteraceae or Compositae family, is a perennial herb with a long history of traditional use.

The expression "feverfew" is derived from the Latin for fever reducer. Evidence of the anti-inflammatory properties of feverfew has been accruing over the last several decades and is now considered well established (Carcinogenesis 2004;25:1449-58).

Photo (c)Courtesy Wikimedia Commons/Dr Paul G Tuli/Creative Commons License

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 (Br. Med. J. [Clin. Res. Ed.] 1985;291:569-73). In addition, feverfew is known for success in treatment for arthritis, as well as its anti-inflammatory activity in blocking phospholipase breakdown of arachidonic acid into prostaglandins and leukotrienes (Dermatol. Surg. 2001;27:759-63; 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 A (Dermatol. Surg. 2001;27:759-63; J. Pharm. Pharmacol. 1990;42:553-7; J. Pharm. Pharmacol. 1987;39:459-65). Parthenolide is obtained as a hydroalcoholic extract of aerial parts of the plant, and is known to inhibit nuclear factor–kappaB (NF-kappaB) and to exhibit antiproliferative properties (Biochem. Biophys. Res. Commun. 2005;332:321-5). Feverfew also contains the potent antioxidant melatonin (Lancet 1997;350:1598-9).

Parthenolide Potency

Parthenolide has been consistently shown to exhibit in vitro antitumor activity (Mol. Cancer Ther. 2005;4:1004-12). 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 that were given parthenolide exhibited later onset of papillomas and significantly fewer papillomas in comparison to mice that were exposed only to UVB but not fed the primary component of feverfew. The in vitro phase of the study, which used cultured JB6 murine epidermal cells, showed that noncytotoxic concentrations of parthenolide pretreatment significantly suppressed UVB-induced activator protein-1 DNA binding and transcriptional activity, as well as JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase signaling activation, all of which might be crucial in the anticancer mechanism of action of parthenolide, according to the authors (Carcinogenesis 2004;25:1449-58). 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;26:2149-56).

In another recent study, investigators found that parthenolide effectively blocked the gene expression mediated by NF-kappaB and the production of bFGF (basic fibroblast growth factor) and MMP-1 (matrix metalloprotease-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;315:624-30).

In addition to its potential activity against skin cancer and photoaging, the feverfew constituent parthenolide 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;332:321-5).

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;49:176-82).

Although several in vitro studies have indicated that parthenolide imparts anti-inflammatory effects, a recent in vivo study with mice demonstrated that the sesquiterpene lactone component of feverfew modestly suppressed only one gene, interleukin-6 after lipopolysaccharide-induced increases (J. Inflamm. (Lond). 2005;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.

A recent finding regarding parthenolide 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, which is often a precursor to cirrhosis and hepatocellular carcinoma (J. Inflamm. [Lond]. 2005;2:6). In hepatoma cells, parthenolide has been found to enhance the apoptosis induced by fenretinide (N-4-hydroxyphenyl retinamide, or 4-HPR), a synthetic anticancer retinoid and an established apoptosis-inducing agent. In a study focusing on the relationship of these two compounds, parthenolide was found to upregulate or downregulate 35 apoptosis-related genes, and its role as an adjuvant anticancer agent against hepatoma was elucidated (Cancer Res. 2005;65:2804-14).

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;5:1147-52). 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, compared with other adenomatous cholangiocarcinoma cells, to parthenolide (Cancer Res. 2005;65:6312-20).

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 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).

Conclusion

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. Recent success has been observed with parthenolide-depleted feverfew. The ability to take a naturally occurring ingredient and improve it by removing an undesirable part of the chemical structure is the future of "natural" skin care, in my opinion. Will we be seeing more of the tweaked ingredients? I believe we will.

Feverfew, a member of the Asteraceae or Compositae family, is a perennial herb with a long history of traditional use.

The expression "feverfew" is derived from the Latin for fever reducer. Evidence of the anti-inflammatory properties of feverfew has been accruing over the last several decades and is now considered well established (Carcinogenesis 2004;25:1449-58).

Photo (c)Courtesy Wikimedia Commons/Dr Paul G Tuli/Creative Commons License

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 (Br. Med. J. [Clin. Res. Ed.] 1985;291:569-73). In addition, feverfew is known for success in treatment for arthritis, as well as its anti-inflammatory activity in blocking phospholipase breakdown of arachidonic acid into prostaglandins and leukotrienes (Dermatol. Surg. 2001;27:759-63; 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 A (Dermatol. Surg. 2001;27:759-63; J. Pharm. Pharmacol. 1990;42:553-7; J. Pharm. Pharmacol. 1987;39:459-65). Parthenolide is obtained as a hydroalcoholic extract of aerial parts of the plant, and is known to inhibit nuclear factor–kappaB (NF-kappaB) and to exhibit antiproliferative properties (Biochem. Biophys. Res. Commun. 2005;332:321-5). Feverfew also contains the potent antioxidant melatonin (Lancet 1997;350:1598-9).

Parthenolide Potency

Parthenolide has been consistently shown to exhibit in vitro antitumor activity (Mol. Cancer Ther. 2005;4:1004-12). 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 that were given parthenolide exhibited later onset of papillomas and significantly fewer papillomas in comparison to mice that were exposed only to UVB but not fed the primary component of feverfew. The in vitro phase of the study, which used cultured JB6 murine epidermal cells, showed that noncytotoxic concentrations of parthenolide pretreatment significantly suppressed UVB-induced activator protein-1 DNA binding and transcriptional activity, as well as JNK (c-Jun N-terminal kinase) and p38 MAP (mitogen-activated protein) kinase signaling activation, all of which might be crucial in the anticancer mechanism of action of parthenolide, according to the authors (Carcinogenesis 2004;25:1449-58). 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;26:2149-56).

In another recent study, investigators found that parthenolide effectively blocked the gene expression mediated by NF-kappaB and the production of bFGF (basic fibroblast growth factor) and MMP-1 (matrix metalloprotease-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;315:624-30).

In addition to its potential activity against skin cancer and photoaging, the feverfew constituent parthenolide 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;332:321-5).

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;49:176-82).

Although several in vitro studies have indicated that parthenolide imparts anti-inflammatory effects, a recent in vivo study with mice demonstrated that the sesquiterpene lactone component of feverfew modestly suppressed only one gene, interleukin-6 after lipopolysaccharide-induced increases (J. Inflamm. (Lond). 2005;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.

A recent finding regarding parthenolide 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, which is often a precursor to cirrhosis and hepatocellular carcinoma (J. Inflamm. [Lond]. 2005;2:6). In hepatoma cells, parthenolide has been found to enhance the apoptosis induced by fenretinide (N-4-hydroxyphenyl retinamide, or 4-HPR), a synthetic anticancer retinoid and an established apoptosis-inducing agent. In a study focusing on the relationship of these two compounds, parthenolide was found to upregulate or downregulate 35 apoptosis-related genes, and its role as an adjuvant anticancer agent against hepatoma was elucidated (Cancer Res. 2005;65:2804-14).

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;5:1147-52). 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, compared with other adenomatous cholangiocarcinoma cells, to parthenolide (Cancer Res. 2005;65:6312-20).

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 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).

Conclusion

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. Recent success has been observed with parthenolide-depleted feverfew. The ability to take a naturally occurring ingredient and improve it by removing an undesirable part of the chemical structure is the future of "natural" skin care, in my opinion. Will we be seeing more of the tweaked ingredients? I believe we will.