Studies on the anti cancer potential of sesquiterpene lactone parthenolide

1 CHAPTER CHAPTER INTRODUCTION 1.1 Parthenolide 1.1.1 Introduction: feverfew and Parthenolide Feverfew (Tanacetum parthenium) is an aromatic perennial herb grown originally in Europe It has been traditionally used as an herbal medicine in treatment of migraine, fever, arthritis and menstrual problems since ancient times In the last few decades, feverfew became especially popular in Britain, France and Canada as a phytomedicine Powder of dried leaves has been made into capsules or tablets for oral consumption The major pharmacological benefits of feverfew include: (i) prevention of migraine, (ii) relief of fever, and (iii) treatment of rheumatoid arthritis and inflammatory disease (Berry, 1984; Johnson et al., 1985) The main chemical constituents of feverfew include sesquiterpene lactones, flavonoid glycosides and monoterpenes (Abad et al., 1995) The most predominant and well studied active component of feverfew is a group of sesquiterpene lactones such as parthenolide, costunolide and germacranolide, etc (Knight, 1995) These sesquiterpene lactones are enriched in the leaves and seeds of the feverfew which are believed to be produced by superficial leaf glands and act as general insect repellents for plants Among feverfew extracts, parthenolide is the principle sesquiterpene lactone responsible for most of the pharmacological effects of feverfew (Knight, 1995) 1.1.2 Chemical structure, metabolism and bioactivities of parthenolide 1.1.2.1 Chemistry: sesquiterpene lactones and parthenolide Chemically, parthenolide belongs to the group of sesquiterpene lactone It was first isolated from feverfew in 1965 (Berry, 1984) Parthenolide is a 4,5-epoxygermacra-(10), 11(13)-dien-12,6-lactone and its structure is shown in Fig 1.1 CH3 CH2 O H3C O O Fig 1.1 Feverfew and chemical structure of parthenolide The molecular structure contains a terpene compounds with fifteen carbon atoms and an exocyclic methylene lactone group, an α-methylene-γ-lactone moiety, which has been shown to process an anti-inflammatory activity The α-methylene-γlactone group has an exceptional ability to react with nucleophiles by Michael type addition (Kupchan et al., 1970) Parthenolide has the ability to alkylate intracellular nucleophiles, such as L-cysteine, glutathione (GSH) and a number of thiol-bearing cellular proteins, to form adducts (Fig 1.2) which are believed to be responsible for its pharmacological effects (Hall et al., 1979; Groenewegen et al., 1986; Knight, 1995) Parthenolide derivative, 11β,13-dihydroparthenolide with saturated exocyclic methylene group completely loses its bioactivity suggesting the biological importance of exocyclic methylene group (Marles et al., 1992) In addition, parthenolide possesses an epoxide moiety, another functional group with alkylating ability, which results in an enhanced bioactivity compared to other sesquiterpene lactones Recently, it reported that the spatial arrangement of the terpenoid skeleton is more important than any other functional groups (Neukirch et al., 2003) which are generally believed to be responsible for the bioactivities of parthenolide Fig 1.2 Formation of parthenolide-thiol adducts 1.1.2.2 Transportation in cell system and bioavailability After administration of parthenolide, it can be quickly transported and absorbed by human cells Khan et al (2003) has reported that parthenolide is predominately transported into human intestinal cells (Caco-2) through passive diffusion which can not be prevented by an inhibitor of multidrug resistance transporter P-glycoprotein (MRP) This report provides the evidence of the bioavailability of the parthenolide in cell culture system (Khan et al., 2003) In the in vivo animal model, although the bioavailability of parthenolide has not been reported, recently work in our laboratory using UVB-induced skin cancer model suggested the bioavailability of parthenolide as parthenolide-feeding showed a delayed onset of papilloma incidence and a significant reduction in papilloma multiplicity (Won et al., 2004) 1.1.2.3 Bioactivities of parthenolide Thiol reactivity As discussed earlier, the chemical reactions of parthenolide involve a covalent conjugation between α,β-unsaturated carbonyl structure of parthenolide with various nucleophilic sulphydryl residues (e.g thiols) resulting in alkylation through Michael type addition The binding of parthenolide with sulphydryl groups present in intracellular proteins may disrupt the normal cellular function of macromolecules The three-dimensional structure of both parthenolide and its potential target are the decisive factors for the steric accessibility of parthenolide to its target Appropriate three-dimensional structure is the essential premise for bioactivities of parthenolide and may provide some extent specificity (Yoshioka et al., 1973) However, the biological consequences and the importance of parthenolide’s thiol reactivity are poorly studied Anti-inflammatory activity Inflammation is an important biological process contributing to wound healing and pathological responses to infection A complex network of signaling factors involved in inflammatory response has been evolved (Coussens and Werb, 2002) Anti-inflammatory activity is one of the most prominent bioactivities of parthenolide Feverfew has been traditionally used as a herbal medicine by ancient Greeks and early Europeans for treatment of inflammatory diseases, such as fever and rheumatoid arthritis (Berry, 1984) In 1989, a double-blind study carried out in the UK, demonstrated the effectiveness of feverfew in treatment of the symptoms of rheumatoid arthritis (Pattrick et al., 1989) which may due to pharmacological inhibition of pro-inflammatory cytokine prostaglandin (PG) synthesis The following in vitro studies further elucidated that feverfew as well as its major bioactive component, parthenolide, are potent inhibitors of macrophage production of release of a group of pro-inflammatory cytokines, including tumor necrosis factor (TNF) and interleukins (IL) (Hwang et al., 1996) and this inhibitory activity are mainly regulated via disruption of nuclear factor - kappaB (NF-κB) signaling pathway (Hehner et al., 1999) and signal transducers and activators of transcription (STAT) pathway (Sobota et al., 2000) Anti-cancer activity It has been suggested that chronic inflammation promotes cancer development in many types of cancers, such as breast, colorectal, and liver cancer (Coussens and Werb, 2002) The potent anti-inflammatory activity of parthenolide implies its potential anti-cancer property Parthenolide has been reported to interrupt cell cycle regulation and induce apoptosis in human cancer cells (Wen et al., 2002) In addition, Patel et al (2000) and his colleagues also demonstrated that pre-treatment of parthenolide greatly sensitizes the human breast cancer cells in response to anticancer drug paclitaxel and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis (Patel et al., 2000; Nakshatri et al., 2004) However, the anti-cancer potential of parthenolide is still largely unknown Further studies, including both in vitro mechanism studies on anti-cancer potential of parthenolide and in vivo animal study, are needed 1.1.3 The molecular mechanisms involved in the bioactivities of parthenolide 1.1.3.1 Effects on NF-κB signaling NF-κB is a highly inducible transcription factor in response to diverse stimulations such as TNFα, ultraviolet (UV), interleukins, endotoxins etc NF-κB activation plays a pivotal role in regulating the inflammatory responses, cell growth/differentiation and apoptosis (Li and Verma, 2002; Karin and Lin, 2002) In the typical NF-κB signaling pathway, NF-κB is a heterodimer formed by RelA (p65) and p50 subunit which are sequestered as an inactive form in the cytoplasm by NF-κB inhibitory protein (IκB) Upon stimulation, the IκB protein is phosphorylated by IκB kinase (IKK), ubiquitinized and degraded by 26s proteosome This process results in unmasking the nuclear localization sequence (NLS) of NF-κB protein, NF-κB nuclear translocation and activation (Li and Verma, 2002) Bork et al (1997), for the first time, screened the inhibitory effects of 54 Mexican Indian medicinal plants on transcription factor NF-κB Their data suggested that parthenolide, the major bioactive sesquiterpene lactone extracted from feverfew, shows a potent inhibitory effect on NF-κB activation at a concentration as low as 5µM (Bork et al., 1997) Later on, Hehner et al (1998) reported that parthenolide inhibits several stimulations (TPA, TNFα, ligation of T cell receptor and hydrogen peroxide)-induced NF-κB activation by blocking the degradation of phosphorylated IκB while the DNA binding activity of NF-κB has not been interfered (Hehner et al., 1998) In a subsequent study, they demonstrated that parthenolide directly inhibits the IKK activity induced by TNFα, while TNFα-inducible mitogen-activated protein kinase (MAPK) signaling pathways (p38 and JNK) are not affected by parthenolide (Hehner et al., 1999) Furthermore, parthenolide is capable of blocking NF-κB activation induced by overexpression of upstream activators of IKK, such as TNF receptor associated factor (TRAF2) and mitogen-activated protein kinase (MEKK1), which lead to a conclusion that parthenolide inhibits TNFα-induced NF-κB activation by targeting the IKK complex (IKC) (Hehner et al., 1999) At the same time, Rungeler et al (1999) screened the inhibitory activity on NF-κB of 28 sesquiterpene lactones including parthenolide Using a computer modeling, they proposed a possible molecular mechanism, which the inhibitory activity of parthenolide may due to the alkylation and cross-linking of two cysteine residues (cys 38 and cys 120) located on the p65 subunit of NF-κB (Rungeler et al., 1999) Subsequently, two hypotheses emerged to explain the inhibitory effect of parthenolide on NF-κB activation First, parthenolide inhibits NFκB activity by direct targeting and inhibiting the IKKβ Single amino substitution in the activation loop (C179A) of IKKβ abolished the parthenolide’s IKKβ inhibitory activity (Kwok et al., 2001) Second, parthenolide suppresses NF-κB activation by direct modification of p65 at cys38 via alkylation, which in turn prevents NF-κB DNA binding (Garcia-Pineres et al., 2001) At present, the possible effects of parthenolide upstream of IKK activation have not been studied 1.1.3.2 Effects on inflammatory-related molecules Cytokines A big family of cytokines plays a pivotal role in inflammatory responses The cytokine signaling is highly complicated and the effect of parthenolide seems to be dependent on specific cell line and cellular contexture During inflammatory responses, NF-κB is the most important regulator of the gene expression of proinflammatory cytokines (Tak and Firestein, 2001) Inhibition of NF-κB pathway is believed to be one of the major mechanisms responsible for anti-inflammatory activity of parthenolide Meanwhile, the inflammatory cytokines, such as TNFα and IL-1 could also activate the NF-κB pathway which in turn promotes the inflammatory response through a positive feedback control (Lucey et al., 1996) The effects of parthenolide on expression of several cytokines have been reported Mazor et al (2000) first reported that parthenolide shows a potent inhibitory effect on IL-8 expression in human respiratory epithelium cells (Mazor et al., 2000) In human macrophages, Kang et al (2001) observed a similar inhibitory effect of parthenolide on IL-12 production induced by LPS The p40 promoter activity of IL-12 which contains a NF-κB binding sequence has been greatly suppressed by parthenolide (5µM) (Kang et al., 2001) As NF-κB regulatory elements have been found in the promoter sequences of many pro-inflammatory cytokines, the inhibitory effects of parthenolide on other cytokine secretion have also been demonstrated In Li-Weber et al (2002)’s report, IL-4, IL-2 and IFN-γ secretion from normal peripheral blood T cells are also suppressed by parthenolide (Li-Weber et al., 2002) All these findings indicate that the parthenolide executes its anti-inflammatory effects by regulating the secretion of pro-inflammatory cytokines at transcriptional level via inhibition of NFκB 5-hydroxytryptamine (5-HT) and anti-serotonergic activity 5-HT is a monoamine neurotransmitter secreted by central nervous system and platelets It is believed that 5-HT plays a central role in migraine pathophysiology (Peroutka, 1990) The anti-secretory activity of feverfew extracts, including parthenolide, was reported in the 1980s (Groenewegen et al., 1986) and parthenolide has been found to possess a potent inhibitory effect on 5-HT secretion and platelet aggregation induced by a number of stimulations (Groenewegen and Heptinstall, 1990) It has also been suggested that parthenolide may act as a low affinity antagonist at 5-HT receptors (Weber et al., 1997) Recently, the inhibitory effects of feverfew and parthenolide on 5-HT have been re-examined again (Mittra et al., 2000) However, the exact mechanisms are still not fully elucidated Cell adhesion molecules (CAM) In the inflammatory process, CAMs, which mediate the interaction between leukocyte and endothelium cells, play a key role to recruit and accumulate leukocytes to the site of inflammation (Ulbrich et al., 2003) Many anti-inflammatory drugs process the inhibitory effect of the CAMs Since feverfew is a well documented anti- inflammatory herbal medicine, the potential effects of its main active component, parthenolide, on CAMs have also been reported Piela-Smith and Liu (2001) first reported that both feverfew extracts and parthenolide greatly inhibited the intracellular cell adhesion molecule-1 (ICAM-1) expression induced by various cytokines stimulation, including IL-1, TNFα and IFNγ (Piela-Smith and Liu, 2001) As the ICAM-1 promoter sequence has a response element potentially regulated by NF-κB, the suppressed expression ICAM-1 is likely due to the inhibitory effect of parthenolide on NF-κB (Melotti et al., 2001) Besides the ICAM-1, the effect of parthenolide on expression of other CAMs has also been addressed Furthermore, (VCAM-1)-induced by IL-4 via JAK2-STAT6 signaling was significantly suppressed by parthenolide (Schnyder et al., 2002) It is interesting to note that this inhibitory effect seems converge to the suppression of STAT6 nuclear translocation and DNA binding by an unknown mechanism and the phosphorylation of STAT6 is not affected by parthenolide (Schnyder et al., 2002) Currently, it is believed that suppression of CAMs expression which alleviates the inflammatory response is one of the mechanisms of anti-inflammatory activity of parthenolide iNOS and NO production Nitric oxide (•NO) is one of the important regulator molecules in inflammatory response The synthesis and release of the •NO are mediated by an inducible isoform of nitric oxide synthase (iNOS) Parthenolide has been demonstrated 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