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.