[Molecular mechanisms of parthenolide's action: Old drug with a new face]

[Molecular mechanisms of parthenolide's action: Old drug with a new face].

Parthenolide, a sesquiterpene lactone derived from the leaves of feverfew (Tanacetum parthenium), is considered a main bioactive component of this herb. Feverfew has been used orally or as an infusion for the treatment of migraine, arthritis, fever, and stomachache. Besides its anti-inflammatory and anti-migraine properties, parthenolide also shows anticancer activities in a variety of cell lines. It contains an alpha-methylene-gamma-lactone ring and an epoxide moiety which are able to interact with nucleophilic sites of biologically important molecules. Parthenolide modulates multiple targets, thereby contributing to its various in vitro and in vivo effects. Inhibition of NF-kappaB activity, constitutive in many types of cancers, via either interaction with IKK or more directly with the p65 subunit of NF-kappaB, is considered one of the main mechanisms of its action. In addition, inhibition of STAT and MAP kinase activities and the induction of sustained JNK activity as well as p53 activity via influencing MDM2 and HDAC1 levels lead to an increased susceptibility of cancer cells to chemo- and radiotherapy. At the epigenetic level, parthenolide reduces HDAC1 level and, by inhibiting DNMT2 activity, induces global hypomethylation of DNA, which can restore the expressions of some suppressor genes. Moreover, this compound reduces the cellular level of GSH in cancer cells, followed by ROS accumulation and apoptosis. A unique property of parthenolide is its ability to induce cell death mainly in cancer cells, while sparing healthy ones and it also protects normal cells from UVB and oxidative stress. More remarkably, it seems to have the potential to target some cancer stem cells. Its wide array of biological activity and low toxicity make parthenolide a very promising drug with multi-pharmacological potential, largely dependent on the cellular context.

Feverfew for Migraine Prophylaxis

Clinical bottom line: Overall, these studies suggest that feverfew may be beneficial for the prevention of migraine attacks. However, the effectiveness has not been established beyond reasonable doubt. More data is needed to determine which dose and formulation should be prescribed, and how effective it is. Future trials should measure clinically relevant outcomes in accordance with International Headache Society (IHS) criteria.
Feverfew (Tanacetum parthenemium L) is a popular herbal remedy recommended for the prevention of migraine. The pharmacological properties of feverfew have been extensively investigated but remain unclear.

Systematic review

Vogler BK, Pittler MH and Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia. 1998; 18:704-708

Date review completed: April 1998

Number of trials included: 5

Number of patients: 196

Control group: placebo

Main outcomes: headache severity and frequency, nausea and vomiting, photophobia

Inclusion criteria were randomised, double-blind, placebo-controlled trials of feverfew mono-preparations taken for migraine prophylaxis. No restriction to language of publication.

Reviewers conducted extensive searches of all main databases and reference lists of retrieved reports, and contacted manufacturers of feverfew preparations. Trials were scored for methodological quality using the Oxford scale (Jadad et al., 1996). Reviewers provided a descriptive summary of included trials, as pooling of data for meta-analysis was not possible.

Findings

Five trials were found, one in form that measured serotonin uptake and platelet activity and is not discussed further here. Four randomised, double-blind, placebo-controlled trials were found reporting on clinical outcomes. All trials scored at least three of five points on the quality scale. Trials varied with respect to dosing schedules and formulations of feverfew, and outcome measures. Only one trial used IHS criteria for migraine definition, diagnostic criteria were unclear in two of the other trials. Three trials were of crossover and one of parallel design. Reviewers did not state if there were any carry-over effects in the crossover studies. One trial had less than ten patients per treatment group. Overall three trials reported results in favour of feverfew over placebo and one found no difference.

One trial randomised 17 patients to 100 mg feverfew daily (capsules containing freeze-dried leaves) or placebo for 24 weeks. All patients had taken raw feverfew leaves every day for three to four years. There was a significant increase in attack frequency in the placebo group (p<0.02), attack frequency remained constant in the feverfew group. Five of eight patients in the feverfew group reported good to excellent effectiveness based on a global assessment of treatment, compared with one of nine in placebo group. There are too few patients to draw meaningful conclusions from these results.

One trial randomised 72 patients to either one capsule dried feverfew leaves daily (dose not stated) or placebo for eight months (crossing over to other treatment after four months). A significant reduction in headache frequency (p<0.005) was reported by the feverfew group compared with placebo. Global assessment of treatment showed feverfew significantly better than placebo (p<0.0001).

One trial randomised 50 patients with IHS definition of migraine to 143 mg feverfew daily (capsule containing an alcoholic extract of feverfew) or placebo for four months (cross over at two months). There was no significant difference in headache frequency or number of workdays lost between the groups.

One trial randomised 57 patients with medical diagnosis of migraine to 100 mg feverfew daily or placebo for two months (cross over after one month). All patients had received 100 mg feverfew daily for two month run-in period. There was a significant difference in all outcomes including migraine severity between feverfew and placebo (p<0.01).

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