Inflammation

, Volume 35, Issue 2, pp 560–565

Parthenolide, a Sesquiterpene Lactone, Expresses Multiple Anti-cancer and Anti-inflammatory Activities

Authors

    • Department of Microbiology, School of Medicine and Brain Korea 21 ProgramJeju National University
    • Cheju National University
  • Young-Sang Koh
    • Department of Microbiology, School of Medicine and Brain Korea 21 ProgramJeju National University
  • Balkrishna Chand Thakuri
    • Department of BiotechnologyTribhuvan University
  • Mika Sillanpää
    • Laboratory of Green Chemistry, LUT Faculty of TechnologyLappeenranta University of Technology
Article

DOI: 10.1007/s10753-011-9346-0

Cite this article as:
Mathema, V.B., Koh, Y., Thakuri, B.C. et al. Inflammation (2012) 35: 560. doi:10.1007/s10753-011-9346-0

Abstract

Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell-specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders.

KEY WORDS

apoptosisanti-cancercytochrome cinflammasomeparthenolideROSTCPfeverfew

INTRODUCTION

Medicinal plants have been widely used for their various curative abilities. Plants synthesize many chemicals both as constitutive products and as secondary metabolites. Extracts of medicinal plants that are traditionally used include aromatic substances, mostly phenolic compounds, or their oxygen-substituted derivatives. Sesquiterpene lactones [1] are plant metabolites which have been widely used in indigenous medical practices for curing high fever, headache, stomachache, toothache, rheumatoid arthritis, menstrual irregularities, and other inflammatory diseases. Parthenolide (PN) is an important naturally occurring sesquiterpene lactone [2] in medicinal plants, found especially in feverfew (Tanacetum parthenium). The nucleophilic nature of its methylene-γ-lactone ring and epoxide group enables rapid interactions with biological sites (Fig. 1). These interactions have been found to be related to its ability to induce oxidative stress, and it shows multiple anti-cancer and pro-apoptotic characteristics. This review describes the major molecular interactions involved in PN-mediated cellular responses.
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Fig. 1

Chemical structure of sesquiterpene lactone parthenolide. A naturally occurring phytochemical in Tanacetum parthenium with multiple medicinal properties.

Parthenolide Suppresses Inflammation by Inhibiting Activity of NF-κB

Nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is made up of homo- and heterodimers of members of the Rel family, which consists of five major proteins: RelA (p65), RelB, c-Rel, NF-κB1, and NF-κjB2. Activated NF-κB is a transcription factor associated with a wide range of cellular responses, including inflammation, immune regulation, survival, and proliferation [3]. Phosphorylation of IκB by IκB kinase (IKK) on the cytosolic domain and subsequent ubiquitination and degradation of IκB leads to activation of NF-κB. The activated NF-κB then translocates to the nucleus and activates transcription of associated genes by binding with the NF-κB promoters [4]. The majority of NF-κB activities are related to TNF-α [5], foreign antigens [5, 6], oxidative stress [6, 7], and exposure to radiation [8]. However, some experimental evidence suggests that amplified activity or constitutive expression of NF-κB is common in cancerous cells [9]. This is supported by the finding that NF-κB regulates expression of hypoxia-inducible factor 1a, an anti-apoptotic gene involved in cancer [10, 11]. Interestingly, PN is found to inhibit IKK-mediated phosphorylation of IκB by blocking the activity of IKK, including that of IKK-α [12] and IKK-β, thus leading to suppression of RelA/p65 activity in acute myeloid leukemia (AML) cells [13]. Parthenolide singly or in combination with its close analog LC-1 has shown anti-cancer effects on human hematopoietic cells including myeloma [7], AML [13], pre-B leukemia, and chronic lymphocytic leukemia [14, 15]. Regarding nuclear proteins, histone deacetylase inhibitors (HDACIs) are classes of compounds associated with the modification of chromatin structure and gene expression. HDACI-related apoptosis has been observed in human leukemia cells [16]. In the context of human AML cells, PN inhibits HDACI-mediated NF-κB activation and promotes SAPK/c-Jun N-terminal kinase (JNK) activation as well as apoptosis. The interaction of PN and HDACIs was associated with disruption of IKK/RelA-mediated NF-κB activation [17].

Parthenolide Acts as Inhibitor of Inflammasomes

Inflammasomes occur as large cytosolic protein complexes. These mainly consist of components that are members of the nucleotide binding and oligomerization domain of the (NOD)-like receptor of the NLR family [17]. Basically, these complexes act as intracellular sensors that detect conserved microbial components [18] in intracellular compartments. Generally, these ligands [19] can be referred to as pathogen-associated molecular patterns (PAMPs). Inflammasomes engage and activate caspase-1 [20], which in turn processes the inactive pro-IL-18 and pro-IL-1β [15] into their corresponding active forms of pro-inflammatory cytokines, IL-18 and IL-1β, respectively [16, 17]. A wide variety of signals and PAMPs from bacteria, viruses and cell necrosis remnants can lead to activation of the Nlrp3 inflammasome. In addition, Nlrp3 activities have been found to be induced by small immunogenic activators and crystalline or aggregated materials [19, 20]. Autoimmunity disorders like gouty arthritis and neurodegeneration are associated with inflammasomes [2123]. Recently, it was suggested that parthenolide is a good inhibitor of the Nlrp3 inflammasome and that this activity is independent of the inhibitory effect of PN on the NF-κB pathway. This inhibitory effect is achieved by PN-mediated direct inhibition [24] of caspase-1 and Nlrp3.

Parthenolide Induces ROS Exclusively in Tumor Cells

Imbalances between the production of reactive oxygen species (ROS) and the ability of biological systems to readily detoxify these reactive intermediates or easily repair the resulting damage leads to oxidative stress [6]. The anti-cancer activity of parthenolide has been suggested to be due to its pro-apoptotic action, which would occur through the activation of p53 [25] and the increased production of ROS [24]. Interestingly, the pro-apoptotic activity is not observed in normal cells, as these elevated levels of ROS are found to be limited to tumor cells [26, 27]. Cell survival and cell death have been found to be strongly related to the intracellular redox status of the cells [28]. NF-κB inhibition and oxidative stress are two of the major known effects of parthenolide [29]. The activity of PN has been found to be related to the nucleophilic reaction of the methylene-γ-lactone ring with glutathione or cysteine thiol (−SH) groups of other target [30] molecules. These redox reactions with thiol groups will in turn activate or inhibit various targets, thus acting as a biological switch for signaling downstream cascades [30, 31]. Even though the suppression activity of PN has been attributed to signal transduction and activation of transcription (STAT), the oxidative stress seems to have a broader range of inhibitory and apoptotic effects on tumor cells [32]. Recently published data shows that PN increases ROS levels in prostate cancer (pc3) cells by activating NADPH oxidase, which results in a cascade of reactions involving the P3K/Akt pathway and FOXO3a, consequently leading to down regulation of the antioxidant enzymes manganese superoxide dismutase and catalase [33]. It is likely that PN acted by inducing ROS-mediated apoptosis of pre-B leukemia cells [34], supporting the anti-cancer activity of this compound. Work on mitochondrial-targeted oxidative stress by PN in colorectal cancer cells [35] describes the activation of the intrinsic cell death pathway which leads to degeneration of the mitochondrial membrane, releasing pro-apoptotic proteins including smac/DIABLO and cytochrome c. This activity is further supported by caspase-8-mediated cleavage of Bid into tBid [35, 36] as a result of PN treatment. Adding to these findings, a recent study on human gastric cancer cell (SGC7901) has shown that PN-mediated mitochondrial damage [11] results in the release of cytochrome c into the cytosol, which consequently controls expression of Bcl-2 family proteins and activates caspase-mediated cell apoptosis.

Parthenolide Induces Thrombopoiesis Through the Inhibitory Activity of NF-κB and Cell Cycle Arrest

Recently, in vitro studies on the effects of parthenolide on human megakaryotic and mouse megakaryocytic cell lines have revealed that PN enhances platelet formation via inhibition of NF-κB. Unlike prostaglandin J2, which enhances platelet production via oxidative stress, PN acts independently by enhancing production directly [37, 38]. It arrests the cell cycle at G0 phase [39] in rat aortic vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest. This is suggested to be due to increased IκB-α expression and reduced Cox-2 expression.

Parthenolide-Mediated STAT Inhibition

STAT proteins are transcriptional factors responding to extracellular ligands that broadly mediate diverse biological functions such as cell proliferation, differentiation, transformation, and apoptosis [40]. Recent publications suggest that parthenolide-mediated effects on death receptors depend on a reduction in levels of phosphorylated and active forms of STAT proteins [41], which may be due to an inhibitory effect of PN on activation of JAK proteins. Among important members of the TNF family, the TNF-related apoptosis-inducing ligand (TRAIL), also known as the Apo-2 ligand, is found to interact with five distinct TRAIL receptors [42, 43]. In hepatocellular carcinoma (HCC) cells, TRAIL-mediated apoptosis [44] was observed via inhibition of STAT3. Supporting this finding, PN is found to increase the total amount of TRAIL receptors R1, R2, and R3 [42] and induce an extrinsic apoptotic pathway in HCC cells. PN-mediated inhibition of IL-6 expression [45] could also be related to the inactivation of STAT3 via phosphorylation at the Tyr705 residue, resulting in a failure of receptor dimerization, and prevention of activation and nuclear translocation of STAT.

Parthenolide Interferes with Microtubule Formation

Microtubules are elongated, hollow, and cylindrical proteinaceous fibers [46] formed by polymerization of α/β-tubulin heterodimers. Studies have shown that parthenolide actively interferes with microtubule formation [47] by reducing impaired control of spindle positioning. As spindle positioning is a factor favoring tumor invasiveness in cancer cells [47, 48], microtubles may be a good target for cancer therapy. Chemical agents that primarily target cell cycle machinery are assumed to be potent anti-cancer drugs [48, 49]. In this regard, parthenolide has primarily been suggested to inhibit activity of a poorly defined enzyme, tubulin carboxypeptidase (TCP). TCP removes a COOH terminal tyrosine residue and this tyrosine can be re-added by the enzyme tubulin tyrosine ligase (TTL). In human cancers, the invasiveness [49] and belligerence of tumor cells has been correlated with suppression of TTL [50, 51]. Even though the underlying mechanism is not clearly understood, PN has been shown to inhibit TCP, thus preventing [48, 49, 52] the accumulation of detyrosinated α-tubulin (Glu-tubulin) and preventing proliferation of malignant cells.

Parthenolide and Its Derivatives May Be Used as Anti-cancer Drugs

Cancer cells are usually unresponsive to multiple drugs due to altered receptors [53], defects in chromosomal segregation and replication [54], modified cell surface proteins and abnormally activated or suppressed key growth factors or inhibitors [55]. Several key molecular agents, including STAT [41], NF-κB [10, 13], and Bcl [29], are abnormally increased in cancer. However, most anti-tumor drugs have narrow applications against cancerous cells because of their high cellular cytotoxicity and relatively low specificity. Parthenolide has been shown to inhibit DNA synthesis in Hela cells and to inhibit several other tumor cell types [44, 56] by multiple mechanisms. Interestingly, parthenolide is among the few reported small molecular compounds demonstrating selective toxicity against leukemia as well as tumor progenitor cells [15, 42]. This is supported by the finding that PN selectively induces apoptosis [42, 57] in both acute and chronic myelogenous leukemia. In colorectal cancer cell line COLO205, parthenolide depletes intracellular thiols and increases ROS and cytosolic calcium levels, resulting in cellular stress [9], which consequently leads to cell apoptosis. Similar effects of PN-mediate mitochondrial damage and cell death [11] in human gastric cancer cell line SGC7901 suggest that parthenolide-induced ROS-mediated apoptosis may be common to many types of cancer cells [29]. Moreover, PN has also been shown to affect the activities of histone deacetylases (HDACs). HDACs are associated with chromatin remodeling [58] and are targets of potent anti-cancer drugs classified as HDACIs. Parthenolide selectively depletes HDAC in cancer cells [59], resulting in an anti-tumorigenic effect. PN is reported to selectively induce apoptosis in cancer cells by increasing intracellular ROS [7, 30, 31] and maintaining activation of JNK [10]. Its relatively simple chemical structure [2, 58] and low molecular weight enables PN to be easily internalized by the cells, resulting in efficient delivery to most cellular targets.

CONCLUSIONS

Parthenolide, a small sesquiterpene lactone, has been shown to have multiple effects on target cells ranging from phosphorylation to transcriptional inhibition activities. The exact interaction mechanisms of PN with NF-κB, STAT, ROS, TCP, HDACs, and other enzymes or transcriptional factors are not well understood. However, the fact remains that PN selectively affects gene regulation or activity and consequently controls of target cells. Here, we have presented the basic proposed models for parthenolide-mediated anti-cancer, anti-inflammatory and pro-apoptotic effects (Fig. 2). Induction of apoptosis in cancerous cells, while at the same time having no effect on normal cells, is one of the major beneficial characteristics of parthenolide. Thus, the cell-specific activity of this naturally available compound and its implications must be seriously considered for further research and development of anti-cancer drugs.
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Fig. 2

Basic models of parthenolide-mediated anti-cancer and anti-inflammatory activities. Parthenolide-mediated inhibition of NF-kB, STATs transcriptional activity, and resulting downregualtion of multiple anti-apoptotic genes transcription results in sensitization of cells to extrinsic apoptotic signals. In addition, induction of oxidative stress and cascade of reactions leading to mitochondrial dysfunction leads to activation of intrinsic apoptosis in cancer cells.

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© Springer Science+Business Media, LLC 2011