Cancer:
Myeloma, ovarian adenocarcinoma, breast, acute myelogenous leukemia, epithelial-to-mesenchymal transition (EMT)

Action: Anti-cancer, anti-inflammatory, inhibits NF-κB, promotes apoptosis

Inhibits NF-κB & Promotes Apoptosis

Parthenolide, a sesquiterpene lactone derived from the leaves of feverfew (Tanacetum parthenium (L.)), 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 anti-cancer 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 radio- therapy. 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 (Koprowska et al., 2010).

Multiple Myeloma

It has been shown that parthenolide is a potent anti-MM-CSC agent. Multiple myeloma (MM) is an incurable plasma cell malignancy where nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor, leaving the cancer stem cells to trigger a relapse. It demonstrated preferential toxicity toward MM-CSCs over non-tumorigenic MM cells. Addition of the bone marrow stromal compartment abrogated andrographolide activity while having no effect on parthenolide cytoxicity. It hence has anti-CSC activity in myeloma, suggesting that it has the potential to improve the survival of patients with MM by eliminating the relapse-causing MM-CSCs (Gunn et al., 2011).

Acute Myelogenous Leukemia

Parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human acute myelogenous leukemia (AML) cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the non-obese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations.

Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor κB (NF-κB), pro-apoptotic activation of p53, and increased reactive oxygen species (ROS) (Guzman, et al., 2005).

PTL is known to be a potent inhibitor of NF-κB (Bork et al., 1997). The mechanism of NF-κB down-regulation appears to occur via inhibition of the IKK complex. Guzman et al. (2005) observed strong inhibition of NF-κB in primary AML cells and speculate that this activity contributes to the efficacy of PTL. However, previous genetic studies using a dominant-negative repressor of NF-κB activity have shown that inhibition of NF-κB alone is not sufficient to mediate the robust cell death observed with PTL. Rather, blockade of the NF-κB pathway appears to sensitize primary AML cells to death and induces a relatively slow spontaneous apoptosis (~50% cell death in 36 h) (Guzman et al., 2002). Similarly, studies by Romano et al. (2000) showed that treatment of primary AML blasts with NF-κB decoy oligonucleotides was not sufficient to induce a strong apoptotic response.

Consequently, PTL must be affecting other pathways relevant to AML-specific survival. One such pathway appears to be mediated by the activity of p53. PTL induced rapid up-regulation of p53 protein with concomitant phosphorylation on serine (Woynarowski & Konopa, 1981).

Ovarian Carcinoma

Results suggest that parthenolide may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of parthenolide appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Parthenolide might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy (Kwak et al., 2013).

Epithelial-to-Mesenchymal Transition (EMT)

Detyrosinated tubulin, a post-translational modification of α-tubulin and a hallmark of stable microtubules, has gained recent attention given its association with tumor progression, invasiveness, and chemoresistance. Also, epithelial-to-mesenchymal transition (EMT) promotes tubulin detyrosination through tubulin tyrosine ligase (TTL) suppression. Given the induction of EMT associated with inflammation and cancer progression, Whipple et al. (2013) tested anti-inflammatory nuclear factor-kappaB (NF-κB) inhibitors on a panel of human breast carcinoma cells to examine their effects on detyrosinated tubulin to identify more specific tubulin-directed anti-cancer treatments.

Breast Cancer

Sesquiterpene lactones, parthenolide and costunolide, selectively decrease detyrosinated tubulin independent of their inhibition of NF-κB. Live-cell scoring of suspended cells treated with parthenolide and costunolide show reduction in the frequency of microtentacles and inhibition of reattachment. Selective targeting of detyrosinated tubulin with parthenolide and costunolide can reduce McTN frequency and inhibit tumor cell reattachment. These actions are independent of their effects on NF-κB inhibition, presenting a novel anti-cancer property and therapeutic opportunity to selectively target a stable subset of microtubules in circulating tumor cells to reduce metastatic potential with less toxicity in breast cancer patients (Whipple et al., 2013).

References

Bork PM, Schmitz ML, Kuhnt M, Escher C, Heinrich M. (1997). Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-kappaB. FEBS Lett, 402:85-90.

Gunn EJ, Williams JT, Huynh DT, et al. (2011). The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma. Leuk Lymphoma, 52(6):1085-97.

Guzman ML, Rossi RM, Karnischky L, et al. (2005). The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cell. Blood, 105(11): 4163–4169. doi: 10.1182/blood-2004-10-4135.

Guzman ML, Swiderski CF, Howard DS, et al. (2002). Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A, 99:16220-16225.

Koprowska K, Czyz M. (2010). Molecular mechanisms of parthenolide's action: Old drug with a new face. Postepy Hig Med Dosw, 64:100-14.

Kwak SW, Park ES, Lee CS. (2013). Parthenolide induces apoptosis by activating the mitochondrial and death receptor pathways and inhibits FAK-mediated cell invasion. Mol Cell Biochem.

Romano MF, Lamberti A, Bisogni R, et al. (2000). Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-kappa B/Rel-specific decoy oligodeoxynucleotides. Gene Ther, 7:1234-1237.

Whipple RA, Vitolo MI, Boggs AE, et al. (2013). Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF- κ B inhibition. Breast Cancer Res,15(5):R83.

Woynarowski JM, Konopa J. (1981). Inhibition of DNA biosynthesis in HeLa cells by cytotoxic and anti-tumor sesquiterpene lactones. Mol Pharmacol,19:97-102.