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Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity
Biomedicine & Pharmacotherapy 106 (2018) 239–246
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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha
Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity Ghader babaeia, Azadeh Aliarabb, Sina Abroona, Yusof Rasmia, Shiva Gholizadeh- Ghaleh Aziza, a b
T ⁎
Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical sciences, Tehran, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Sesquiterpene lactone Natural compounds Anticancer drugs
Cancer is one of the most dangerous diseases that are rapidly increasing globally. After heart disease, it is the second leading cause of death, accounting for seven million deaths each year. Chemotherapy is the use of cytotoxic drugs on cancer cells. But the use of common chemotherapy drugs poses a problem due their high side effects and low efficacy. As a result, efforts are on to find new potent compounds with low side effects. The compounds extracted from plants have been studied in this regard due to their prevalence. Sesquiterpene lactones are a group of natural compounds that were first detected in Asteraceae dark plants. These compounds exercise their effects by reacting with functional groups available on proteins and enzymes, especially the thiol group. Owing to the high side effects as an antitumor synthetic drugs, efforts are being made to find drugs with high efficiency and low side effects. Their high structural ranges have attracted the attention of many researchers as a potential source of new anticancer drugs.
1. Introduction While many efforts have been made in recent decades to improve cancer treatment, chemotherapeutic agents have been recognized to be highly effective and have successfully reached a clinical stage; cancer is still one of the causes of death in many countries around the world. Therefore, one of the main priorities of many pharmaceutical companies and research organizations is to find new therapies for cancer treatment [1]. A lot of research has been done to find more effective therapeutic compounds with fewer side effects. However, the two major shortfalls with anticancer drugs are multi-resistance and the low efficacy in in vivo systems due to low bioavailability [2]. The ultimate goal of chemotherapy treatment is to search for compounds with a selective effect on cancer cells. One of the ways to improve the possibility of solving this problem is to use plants to treat cancer. From a distant past, plants in all cultures have been used as a source of medication due to their health benefits. Secondary metabolites are not essential for the growth and development of the organism, but they serve as a mechanism for adaptation to the environment [3]. The term natural product is synonymous to the term secondary metabolite. These compounds have a diverse structure and a molecular weight of less than 3000 Da. The data from Newman et al, [4] review showed that, natural products and/or their novel structures used for the purpose of final drug discovery, is still at large.
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For instance, in cancer research between 1940 and 2014, of the 175 approved small molecules, 131 (75%) were other than synthetic, with 85 (49%) actually being either natural products or directly derived therefrom. More than 80,000 species of 250,000 known herbs are used for health and therapeutic purposes, and more than 60% of the commonly used anticancer drugs are made from natural resources. A wide range of biological activities and a wide variety of plant-derived compounds have led to an effective continuation of plant screening to find chemotherapy and chemo-proactive compounds [5]. Sesquiterpene lactones exhibit great structural diversity and a broad range of biological activities and are found mainly in genus from Asteraceae family like Artemisia, Arnica, Ambrosia, Helenium, Tanacetum, and Vernonia (Fig. 1) [5,6]. 2. Sesquiterpene lactones Asteraceaes are a highly developed group of plants, whose members are rich in bioactive compounds (secondary metabolites), including polyacetylenes, diterpene and sesquiterpene lactones [7]. These compounds include a large group of low molecular weight secondary metabolites [6] that have various biological activities. These compounds are the largest group of natural compounds having more than 5000 different structures, most of which are found in Asteraceaes. These
Corresponding author at: Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, 5756115111 Urmia, Iran. E-mail address: [email protected] (S.G.-.G. Aziz).
https://doi.org/10.1016/j.biopha.2018.06.131 Received 10 February 2018; Received in revised form 24 June 2018; Accepted 25 June 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
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Fig. 1. Some plants that contains sesquiterpene lactones. a. Chamazulene (German chamomile). b. Helianthus annuus (common sunflower). c. poppy (Papaveraceae). d. Leucanthemum vulgare (oxeye daisy). e. Artemisia (Mugworts plant). A. Upper left b. Upper right c. Middle d. Lower left e. Lower right.
the presence of α-methylene-γ-lactone and the biologic activity of sesquiterpene lactones. Subsequent studies showed that this structure exhibited biological activity in the exo mode and did not have this effect in the endo mode. The α-methylene-γ-lactone section of sesquiterpene lactones is connected to the nucleophilic structures of the target molecules through Michel's reaction, such as the cysteine thiol amino acid group in proteins [9]; they have their effects and change the spatial and chemical structure through alkylating transcription factors and various enzymes. Through Michel's reaction, sesquiterpene lactones cause the enzymes and transcription factors to be alkylated in their thiol groups (Fig. 2). This reaction is the main factor behind the biological effects of the sesquiterpene lactones [7]. On one hand, studies have shown that higher lipophilicity of the side chain of the sesquiterpene lactones leads to a greater ability to enter the cell, resulting in high cytotoxicity, and, on the other hand, an allowed limit is also defined by steric hindrance for this property. This lipophilicity reduces the solubility in water by reducing the bioavailability of these compounds [9]. Many studies have been done to increase bioavailability and solubility. One of these methods is the addition of amino group to the α-methylene-γ-lactone section of the compounds to increase its solubility [11]. Another method for the parthenolide sesquiterpene lactones is the use of nanoparticle derivatives of this compound, which increases their solubility and bioavailability. This method increases the anticancer effects of the derivative compound compared to the parthenolide [12]. Another feature that affects the biological activity of these compounds is structural flexibility, which increases the biological activity of these compounds [9]. Several biological activities, including antimicrobial activity [13], antimigraine14, digestive and analgesic [14], anticancer, and the enhancement of cardiac muscle functions [15] can be mentioned for these herbal compounds. Tada et al. [16], described a general technique for synthesizing iminium tetrahydrothiophene encapsulated in dimeric Nuphar alkaloids. Sulfur atom of thiaspirane pharmacophore was electrophilic. This α-thioether reacts with glutathione or thiophenol at ambient temperature to break the CeS bond and resulting in the formation of a disulfide.
Fig. 2. An overview of Michel's reaction; binding to the thiol groups on the enzymes and proteins that alter the structure and function of the sesquiterpene lactone reaction10.
compounds have been considered owing to their high therapeutic activities [5,8]. They are classified into five groups in terms of structure: 1. Germacranolides, 2. Elemanolides, 3. Eudesmanolides, 4. Guaianolides, and 5. Pseudoguaianolides. The different biological activities of sesquiterpene lactones are related to the difference in the structures of these compounds [9]. Sesquiterpenes are natural terpenoids with a 15-carbon skeleton. This compound can be hydrocarbon or oxygen-based and contain alcohol, ketone, aldehyde, acid, and the lactone group. When the Sesquiterpene skeleton contain a lactone, the compound is called sesquiterpene lactone, and “oid” is added to it as a suffix [5]. Sesquiterpene lactones are one of the super families of sesquiterpene consisting of colorless, crisp, and dry lipophilic compounds made up of three isopropyl units [7,9]. These compounds have low thermal stability and, in most cases, reversed-phase high-performance liquid chromatography are used to isolate and analyze these compounds. More attention is paid to them for their biological and pharmacological activities [5].
3. Sesquiterpene lactone nucleus The biological activity of sesquiterpene lactones depends on three biochemical properties of these compounds: 1. alkylating center reaction, 2. side chain and lipophilicity, and 3. molecular geometry and electronic properties. These activities of sesquiterpene lactones are due to the structure of α-Methylene-γ-lactone [9]. In 1969, Hartwel and Abbott [10] investigated more than 50 types of sesquiterpene lactones and found an indirect relationship between 240
p53, Bax, caspase9, caspase3
Bax, Bid, tBid, caspase 3 and caspase 8, increased release of cytochrome C from the mitochondria
HepG2 Cell Renal cancer cell lines
Gastric cancer cell line SGC7901
241
Cervical carcinoma SiHa cell
Lung adenocarcinoma cell line A549 cells
Human U2OS cells
caspases 8, 9, 3, 7 , ROS, bax, p53, p21,
Lung cancer cells
Deoxyelephantopin
Costunolide
TIMP-2, activated p-JNK, p-p38, NF-κB and IκBα expressions
UM-SCC-10A cell line
Isoalantolactone
Bax, Cyt-c, JNK, caspase-3 and caspase-9, reactive oxygen species (ROS) generation and ER stress-induced mitochondrial dysfunction GRP78,IRE1α,, ASK1, JNK, ROS generation,
p53, p21, Bax, mitochondrial release of cytochrome c , activation of caspase-3 ,
MMP-2, MMP -9,
SW-872 (human liposarcoma), SW-982 (human synovial sarcoma) and TE-671 (human rhabdomyosarcoma)
Costunolide and dehydrocostus lactone
GSH depletion, inhibition of STAT3 activation, Bax generation ROS, Bax caspases-8, caspases -9, caspases -3, PARP, Bax Generation ROS, P53, Bax
HepG2 Cell Human cervical cancer cell Lung Squamous Cancer SK-MES-1 Cell glioblastoma cells
Alantolactone
Increse
Parthenolide
Effect on cancer cells
Type of cancer cells
Name Compounds
Table 1 Summary of the effects sesquiterpene lactones on the factors involved in cancer.
[58]
Bcl-2
[59]
[57]
[56]
[55]
[54]
[51] [52] [53] [23]
[49,50]
[47] [48]
MMP-2, MMP-9, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, p-ERK1/2 and p-Akt, Bcl2, Bcl-Xl, pSTAT3, cdc2, cyclin B1, p-Akt, p-mTOR,
cyclin D, Bcl-2, reduction of mitochondrial membrane potential,
cyclin B1, CDK1, CDK2,
ROS generation Bcl-2, caspase-3 activation GSH, Bcl-2 Bcl-2, CDK4, CDK6, cyclin D3, cyclin D1 GSH, Bcl2, cytochrome, Activation of caspases 3, caspases 9, poly ADP-ribose polymerase
Bcl-2 VEGF, decreased nuclear localization of NF-kB and phosphorylated NF- kB protein, MMP-9, Bcl-xL, Cox-2 Bcl-2 NF-κB
Decrease
Reference
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causing the growth, proliferation and metastasis of cancer cells [21]. Moreover, studies on EM23 indicate that this substance inhibits the expression of thioredoxin and thioredoxin reductase and disrupts the balance of redox cells. On the other hand, the reduction of thyroxine activates ASK1, and this activates the downstream ASK1 factors, namely, p38, JNK and ERK MAPKs, resulting in the induction of apoptosis. This compound also inhibits the activity of NF-kB activated by TNF-α [22]. Dimethylaminopartenolide (DMAPT) has been recently evaluated as one of the compounds of the sesquiterpene lactones in clinical trials in Phase 1 for solid tumors [9]; it causes anticancer effects with various mechanisms including ROS generation, gene expression change through epigenetics, the targeting of the sarcoplasmic reticulum Ca2+ ATPases (SERCA), NF-kB and p53 signaling pathways, angiogenesis and metastasis [23]. Based on a study conducted on three cell lines; NIH 3T3, MCF-7 and Hela, the anticancer effects of sesquiterpenes have been strongly confirmed through the signaling pathways of NF-kB and p53 [24]. Recent studies have shown that sesquiterpene lactones cause changes in cell redox balance and oxidative stress in cells (Fig. 4). Oxidative stress involves the accumulation of free radicals oxygen inside, which can lead to the spread of cancer. On the other hand, increased free radicals can induce apoptosis through mitochondrial effects. Glutathione (GSH) is one of the antioxidant factors, having a high concentration in cancerous cells compared to normal cells. Recent studies on parthenolide sesquiterpene lactones have shown that this compound increases the free radicals through the inhibition of NF-kB, signal transducer and activator of transcription 3 (STAT3) and also P53. Parthenolide inhibits the decomposition of this inhibitory protein through the binding to the IkB-α subunit acting as an NF-kB inhibitor. Conversely, studies show that, in the normal state, the inner surface of the cell is restored compared to the external part, but in cancer cells, this state is reversed and the outer region is restored more than the internal part. In this situation, the presence of the extracellular thiol group can be a suitable factor for the selective action of parthenolide sesquiterpene lactones [25]. Matsuda et al. reported the isolation and characterization of active component from the leaves of L. nobilis, structure-activity relation of active component of the plant, the description of the effects of costunolide and dehydrocostus lactone which possessed a higher potency
Their investigation suggest that the sulfur of Nuphar dimers is capable of reacting as an electrophile in cell environments and sulphur can activate cells retrodimerization. Furthermore, Jansen et al. reported the synthesis of asymmetric dimeric thiaspirane nuphar alkaloid from 3-methyl-2-cyclopentenone through eight step process. This route of synthesis is dependent upon a useful method for tandem reductive cyclopentenones allylation, redox manipulation minimization and interconversions of other functional groups. The catalytic asymmetric method to the nuphar quinolizidine family is yet to be fully explored [17]. 4. Anticancer properties of sesquiterpene lactones Sesquiterpene lactones are one of the important nucleus in medicinal plants. However, recent anticancer activities of different types of sesquiterpene lactones (Table 1) have attracted the attention of many researchers. Extensive research has been carried out to express the anticancer activity, molecular mechanism, and chemotherapeutic and chemoprotective potential of these compounds [19]. Inhibition of the signaling pathway of Nuclear Factor-kB (NF-kB) is one of the mechanisms by which sesquiterpene lactones produce their anticancer effects (Fig. 3). NF-kB in cancer cells has a major role in inhibiting apoptosis, induction of metastasis, cell proliferation, cell transformation, invasion, metastasis, resistance to chemotherapy, and resistance to radiotherapy [5]. Studies have shown that one of the common goals of sesquiterpene lactones is to inhibit the NF-kB pathway. This factor is made up of two subunits; p50 and p65 in the normal state, which is inhibited by cytoplasmic inhibitor of kB (IkB). At the time of stimulation of the cells by cytokines, the Protein kinase IKKβ [9] is activated, causing phosphorylation and ubiquitinization of IkB, and, eventually, degradation by the proteasome complex. As a result, inhibition was removed from NF-kB, and dimers of p50 and p65 enter the nucleus and increase the expression of target genes [20]. Dihydrocastenolide is a sesquiterpene lactone that applies its anticancer effects through the NFkB pathway. This compound inhibits the IKKβ kinase, which seems to be done by connecting to the ATP binding site, inhibiting NF-kB and the use of p300, thereby leading to the accumulation of these factors in the cytoplasm. Consequently, the level of COX-2 expression decreases in melanoma cancer. This factor is greatly enhanced in melanoma cancers,
Fig. 3. The Sesquiterpene lactone is largely affected by two path ways. The result of inhibition of these two pathways by using lactogenic sesquiterpenes can inhibit cancer cells. 242
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Fig. 4. Mechanism of antioxidant effect of sesquiterpene lactone.
deoxyelephantopin (DET) had anti-tumorigenic effect and if they can upregulate pro-inflammation of NF-κB in tumor cells? Several breast cancer cells such as MDA-MB-231, MDA-MB-453, MDA-MB-468, MCF7, and C6-glioma cell lines were used. IDET was found to inhibit the growth of different glioma and breast cancer cell lines in a time and dose dependent manner. IDET was more potent compared to DET. The sesquiterpene stimulated apoptosis in tumor cell and suppressed the expression of tumor cell survival. De Ford et al. [28] results showed that sesquiterpene lactones from S. sonchifolius have an outstanding cytotoxicity, most especially polymatin B and fluctuanin and may probably be therapeutically be synthesized to make useful drugs. However, more investigations is suggested to gain more insights in the mechanism of necroptosis and apoptosis and particularly their potency has to be confirmed in vivo. Another study showed that alantolactone act as an anticancer agent by inhibiting the thioredoxin reductase enzyme. This compound increases the oxidized form of this enzyme by thioredoxin reductase inhibition, and also induces apoptosis in HeLa cells by increasing the amount of free radicals oxygen [29]. A recent study has also shown that the parthenolide and its water-soluble form, DMAPT, increase the production of hydrogen peroxide by activating the NADPH oxidases (NOXs) in Triple-negative breast cancer (TNBCs) cells in the early hours after treatment with these compounds. These two substances also reduce the expression of the factor Nrf2, which is an essential in the production of antioxidant proteins. Long-term treatment with this substance (12–24 h) increases the level of superoxide anions and highly reactive oxygen species, while decreasing superoxide dismutase (SOD) and catalase (CAT) at the same time [30]. In a study, Ozer et al. [18] screened thirty-four methanolic plant extracts for the downregulation of NFkappaB activity using a NFkappaB-luciferase reporter gene assay. They observed that the downregulation of NFkappaB activity was found in the extracts of rhizome and leaf of Nuphar, which was traced to a mixture of thionupharidines and/or thionuphlutidines (dimeric sesquiterpene thioalkaloids). Their findings showed that NUP downregulates the NFkappaB pathway acting as a sensitizer to traditional chemotherapy, this lead to the growing interest of this active compound for the treatment of cancer. Matsuda et al. [31] isolated four monomeric sesquiterpene alkaloids and seven dimeric sesquiterpene thioalkaloids from N. pumilum rhizomes using methanol. The extract obtained decreases B16 melanoma cells invasion across collagen-coated filters. The thiohemiaminal
Fig. 5. Structures of different sesquiterpene lactones compounds referred to in the text [7].
than other sesquiterpenes, on iNOS and heat shock protein (HSP) 72 activation, sesquiterpene lactones from bay leaf showed potent downregulation effects on NO synthesis in LPS-activated macrophages [26] (Fig. 5). Ichikawa et al. [27] examined if isodeoxyelephantopin (IDET) and 243
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continuation of the cell cycle in the S phase and stimulating apoptosis by inhibiting the function of STAT3 and NF-kB. Thus, alantolactone inhibit the activity of NF-kB by inhibiting p65 and TNF-α and IL-6 induction on STAT3. Moreover, the inhibition of the STAT3 phosphorylation and the inhibition of the function of its target genes are similar to survivin [44]. On the other hand, these compounds can produce antitumor properties through changes affecting the epigenetic process. One of the characteristics of various tumors is the 5′-CpG islands of hypermethylation. The hypermethylation of tumor suppressor genes causes these genes to be mutated, which leads to cancer. Studies have shown that the parthenolide reduce the amount of methylation by inhibiting the catalytic domain DNMT1 enzyme and decreasing activity of this enzyme, which acts as an inhibitor of hypermethylation [45]. Histone deacetylases are a group of enzymes that play a major role in epigenetic changes in chromatin, inhibitors of this enzyme are one of the promising therapies. The inhibitors of this enzyme affect the histone deacetylases due to non-specific activity. Parthenolide is a novel inhibitor compound that specifically inhibits HDAC1, but has no effect on classes 2 and 3 of histone deacetylases [46]. The plants of the genus Inula (Asteraceae) are distributed across Africa, Asia, Europe, and most of these plants have long been employed in folk medicine. This plant genus is highly rich in sesquiterpenoids. Cytotoxic and anticancer properties of Inula sesquiterpenoids have been studied extensively since 1970s. A potential compound, Japonicone A, which is a dimeric sesquiterpene lactone from traditional herb Inula japonica, has demonstrated potent in vitro and in vivo anti-tumor activity against Burkitt's lymphoma. Apoptosis induction in cancer cells is a potential method of treatment in tumor therapy. Hamzeloo-Moghadam et al. [60] showed that britannin, a sesquiterpene lactone, possesses antiproliferative activity on the MDA-MB-468 and MCF-7 human breast tumor cells. Hoechst 33,258 staining, Annexin V/propidium iodide (PI) staining, and caspase-3/9 activity assay showed that britannin is capable of inducing apoptosis in the two cell lines. Analysis by western blot showed that bcl2 expression was downregulated significantly in response to treatment by britannin, whereas Bax protein was upregulated, which corresponds with p53 upregulation. In addition, britannin also stimulated reactive oxygen species (ROS) build-up which in turn activated the loss of mitochondrial transmembrane potential (ΔΨm) and subsequently cytochrome c was released from the mitochondria into the cytosol. Collectively, these results proposed that britannin hinders the growth of MDA-MB-468 and MCF-7 breast cancer cells via mitochondrial apoptotic pathway activation and may potentially finds application as an active ingredient in breast cancer therapy. Bosco et al. [61] listed the sesquiterpenes that attack cells in mitosis assessing biological data that assist those observations. Considering mitosis biochemical complexity, they proposed that sesquiterpenes subsets possess a distinct chemical structure capable of targeting a precise protein(s) required for mitosis, this gives a new perspective of sesquiterpene chemical biology.
structure with the 6-hydroxy group in thioalkaloids is crucial for potent activity. The alkaloid constituent as well as the main dimeric sesquiterpene thioalkaloid significantly inhibited the formation of lung cancer [31]. In another separate study, Ozer et al. [32] assessed the effect of leaf and rhizome extracts (NUP) in a B16 melanoma experimental murine lung metastasis model and its potential to affect the NF-κB and ERK pathways in several cell lines. They observed that NUP and standard anticancer drug (cisplatin) combination therapy was synergistic and decreases the load of lung metastatic. Furthermore, the treatment with NUP downregulated TNFα-induced IκBα degradation, so as NF- κB nuclear translocation. NUP induced ERK upregulation was also observed, and its downregulation prevented NF-κB inactivation by NUP. 5. Mechanism of antioxidant properties elucidation by sesquiterpenes Recently, studies on non-small lung cancer (NSCLC) cell lines (A549 and H522) and the immortalized human bronchial epithelial cell line (BEAS2B), transitional cell cancer (TCC) cell lines (UMUC-3, HT-1197 and HT-1376), and bladder papilloma (RT-4) have shown that DMAPT inhibits the connection of NF-kB to DNA and also activates JNK. This condition reduces anti-apoptotic, TRAF-2, and XIAP proteins, increases the amount of p21 and p73 proteins, and cyclin D1 inhibition, ultimately inhibiting the cell cycle and inducing apoptosis [33]. STAT3 is another factor that is controlled by the sesquiterpene lactones. This factor is abnormal in many cancers and has a tumorigenic effect. In cancer cells, this compound leads to apoptosis inhibition, metastasis induction, cell proliferation, cellular invasion, and eventually tumor progression [34]. Alantolactone is one of the sesquiterpene lactones that specifically inhibit STAT3 activity. The possible binding to the SH2 domain of STAT3, inhibits the activity of this transcription factor. It also inhibits translocation to the nucleus and bind to specific DNA- response elements in target gene promoters. It, thus, inhibits the expression of target genes, such as cyclin D1, COX-2, c-myc, mmp-9 and CXCR4, resulting in cell invasion in the G2/M phase and inhibition of metastasis and cellular invasion [35]. However, recently, a mechanism has been proposed for inhibiting STAT3. Cynaropicrin, a sesquiterpene lactone increase free radicals by changing the balance of [GSH]/[GSSG]. The [GSH]/[GSSG] imbalance in cells causes S-glutathionylation of amino acids in many sensitive proteins [36]. One of these proteins is STAT3, which results in STAT3 S-glutathionylation. These post-translational modification cause interference in STAT3 phosphorylation and the inhibition of activation of this transcription factor, the expression of bcl2, and survivin, and ultimately the induction of apoptosis [36]. Such post-translational modification and STAT3 inhibition have been also observed for dehydrocostus lactone and costunolide [37]. One of the reasons for the inhibition of the STAT3 binding to its binding site on the related DNA is probably the oxidation of the amino acid cysteine associated with the binding domain to the DNA by free radicals produced by sesquiterpene lactones [38]. Recent studies have shown that sesquiterpene lactones, the natural substance of tetrahydrofuran-2 pyran have anticancer effects in various human cancers: in colon cancer (HCRC) they activate both apoptosis pathways that are dependent on and independent of caspase [39]; in cervical cancer, they decrease the expression of bcl-2 and increase the expression of p53 [40]; in HL-60 cell leukemia, activate and induce apoptosis through oxidative stress [41]; in bladder cancer of the T24 cell line, activate MAPK-p38 and inhibit the Akt pathway, causing a loss of balance in the mitochondrial membrane [42]; in breast cancer; mutations in HER2 and its receptors. There are several signaling pathways for the incidence of cancer, such as the PI3K/PTEN/Akt/mTOR, and the Ras/Raf/Mek/Erk signaling pathways. Altolactone can inhibit tumorigenicity and tumor progression by inhibiting the PI3K/PTEN/Akt/mTOR pathways [43], and, in prostate cancer, by inhibiting cell proliferation and preventing the
6. Conclusion Sesquiterpene lactones elicit an anticancer effects through a changes in the redox cell balance and their impact on various signaling pathways, especially the NF-kB pathway and STAT3. These activities lead to the reduction in the expression of factors involved in cell cycles, the increase in apoptotic factors, and the reduction of anti-apoptotic, metastasis, and cellular invasion factors. On the other hand, the production of free radicals induces apoptosis and has effects on the pathways mentioned in various cells. The nucleus of sesquiterpene lactones is essential for the development of a novel active terpenoids which may be helpful for cancer therapy.
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Declaration of interest
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Application of sesquiterpene lactone: A new promising way for cancer therapy based on anticancer activity Ghader babaeia, Azadeh Aliarabb, Sina Abroona, Yusof Rasmia, Shiva Gholizadeh- Ghaleh Aziza, a b
T ⁎
Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical sciences, Tehran, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Sesquiterpene lactone Natural compounds Anticancer drugs
Cancer is one of the most dangerous diseases that are rapidly increasing globally. After heart disease, it is the second leading cause of death, accounting for seven million deaths each year. Chemotherapy is the use of cytotoxic drugs on cancer cells. But the use of common chemotherapy drugs poses a problem due their high side effects and low efficacy. As a result, efforts are on to find new potent compounds with low side effects. The compounds extracted from plants have been studied in this regard due to their prevalence. Sesquiterpene lactones are a group of natural compounds that were first detected in Asteraceae dark plants. These compounds exercise their effects by reacting with functional groups available on proteins and enzymes, especially the thiol group. Owing to the high side effects as an antitumor synthetic drugs, efforts are being made to find drugs with high efficiency and low side effects. Their high structural ranges have attracted the attention of many researchers as a potential source of new anticancer drugs.
1. Introduction While many efforts have been made in recent decades to improve cancer treatment, chemotherapeutic agents have been recognized to be highly effective and have successfully reached a clinical stage; cancer is still one of the causes of death in many countries around the world. Therefore, one of the main priorities of many pharmaceutical companies and research organizations is to find new therapies for cancer treatment [1]. A lot of research has been done to find more effective therapeutic compounds with fewer side effects. However, the two major shortfalls with anticancer drugs are multi-resistance and the low efficacy in in vivo systems due to low bioavailability [2]. The ultimate goal of chemotherapy treatment is to search for compounds with a selective effect on cancer cells. One of the ways to improve the possibility of solving this problem is to use plants to treat cancer. From a distant past, plants in all cultures have been used as a source of medication due to their health benefits. Secondary metabolites are not essential for the growth and development of the organism, but they serve as a mechanism for adaptation to the environment [3]. The term natural product is synonymous to the term secondary metabolite. These compounds have a diverse structure and a molecular weight of less than 3000 Da. The data from Newman et al, [4] review showed that, natural products and/or their novel structures used for the purpose of final drug discovery, is still at large.
⁎
For instance, in cancer research between 1940 and 2014, of the 175 approved small molecules, 131 (75%) were other than synthetic, with 85 (49%) actually being either natural products or directly derived therefrom. More than 80,000 species of 250,000 known herbs are used for health and therapeutic purposes, and more than 60% of the commonly used anticancer drugs are made from natural resources. A wide range of biological activities and a wide variety of plant-derived compounds have led to an effective continuation of plant screening to find chemotherapy and chemo-proactive compounds [5]. Sesquiterpene lactones exhibit great structural diversity and a broad range of biological activities and are found mainly in genus from Asteraceae family like Artemisia, Arnica, Ambrosia, Helenium, Tanacetum, and Vernonia (Fig. 1) [5,6]. 2. Sesquiterpene lactones Asteraceaes are a highly developed group of plants, whose members are rich in bioactive compounds (secondary metabolites), including polyacetylenes, diterpene and sesquiterpene lactones [7]. These compounds include a large group of low molecular weight secondary metabolites [6] that have various biological activities. These compounds are the largest group of natural compounds having more than 5000 different structures, most of which are found in Asteraceaes. These
Corresponding author at: Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, 5756115111 Urmia, Iran. E-mail address: [email protected] (S.G.-.G. Aziz).
https://doi.org/10.1016/j.biopha.2018.06.131 Received 10 February 2018; Received in revised form 24 June 2018; Accepted 25 June 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
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Fig. 1. Some plants that contains sesquiterpene lactones. a. Chamazulene (German chamomile). b. Helianthus annuus (common sunflower). c. poppy (Papaveraceae). d. Leucanthemum vulgare (oxeye daisy). e. Artemisia (Mugworts plant). A. Upper left b. Upper right c. Middle d. Lower left e. Lower right.
the presence of α-methylene-γ-lactone and the biologic activity of sesquiterpene lactones. Subsequent studies showed that this structure exhibited biological activity in the exo mode and did not have this effect in the endo mode. The α-methylene-γ-lactone section of sesquiterpene lactones is connected to the nucleophilic structures of the target molecules through Michel's reaction, such as the cysteine thiol amino acid group in proteins [9]; they have their effects and change the spatial and chemical structure through alkylating transcription factors and various enzymes. Through Michel's reaction, sesquiterpene lactones cause the enzymes and transcription factors to be alkylated in their thiol groups (Fig. 2). This reaction is the main factor behind the biological effects of the sesquiterpene lactones [7]. On one hand, studies have shown that higher lipophilicity of the side chain of the sesquiterpene lactones leads to a greater ability to enter the cell, resulting in high cytotoxicity, and, on the other hand, an allowed limit is also defined by steric hindrance for this property. This lipophilicity reduces the solubility in water by reducing the bioavailability of these compounds [9]. Many studies have been done to increase bioavailability and solubility. One of these methods is the addition of amino group to the α-methylene-γ-lactone section of the compounds to increase its solubility [11]. Another method for the parthenolide sesquiterpene lactones is the use of nanoparticle derivatives of this compound, which increases their solubility and bioavailability. This method increases the anticancer effects of the derivative compound compared to the parthenolide [12]. Another feature that affects the biological activity of these compounds is structural flexibility, which increases the biological activity of these compounds [9]. Several biological activities, including antimicrobial activity [13], antimigraine14, digestive and analgesic [14], anticancer, and the enhancement of cardiac muscle functions [15] can be mentioned for these herbal compounds. Tada et al. [16], described a general technique for synthesizing iminium tetrahydrothiophene encapsulated in dimeric Nuphar alkaloids. Sulfur atom of thiaspirane pharmacophore was electrophilic. This α-thioether reacts with glutathione or thiophenol at ambient temperature to break the CeS bond and resulting in the formation of a disulfide.
Fig. 2. An overview of Michel's reaction; binding to the thiol groups on the enzymes and proteins that alter the structure and function of the sesquiterpene lactone reaction10.
compounds have been considered owing to their high therapeutic activities [5,8]. They are classified into five groups in terms of structure: 1. Germacranolides, 2. Elemanolides, 3. Eudesmanolides, 4. Guaianolides, and 5. Pseudoguaianolides. The different biological activities of sesquiterpene lactones are related to the difference in the structures of these compounds [9]. Sesquiterpenes are natural terpenoids with a 15-carbon skeleton. This compound can be hydrocarbon or oxygen-based and contain alcohol, ketone, aldehyde, acid, and the lactone group. When the Sesquiterpene skeleton contain a lactone, the compound is called sesquiterpene lactone, and “oid” is added to it as a suffix [5]. Sesquiterpene lactones are one of the super families of sesquiterpene consisting of colorless, crisp, and dry lipophilic compounds made up of three isopropyl units [7,9]. These compounds have low thermal stability and, in most cases, reversed-phase high-performance liquid chromatography are used to isolate and analyze these compounds. More attention is paid to them for their biological and pharmacological activities [5].
3. Sesquiterpene lactone nucleus The biological activity of sesquiterpene lactones depends on three biochemical properties of these compounds: 1. alkylating center reaction, 2. side chain and lipophilicity, and 3. molecular geometry and electronic properties. These activities of sesquiterpene lactones are due to the structure of α-Methylene-γ-lactone [9]. In 1969, Hartwel and Abbott [10] investigated more than 50 types of sesquiterpene lactones and found an indirect relationship between 240
p53, Bax, caspase9, caspase3
Bax, Bid, tBid, caspase 3 and caspase 8, increased release of cytochrome C from the mitochondria
HepG2 Cell Renal cancer cell lines
Gastric cancer cell line SGC7901
241
Cervical carcinoma SiHa cell
Lung adenocarcinoma cell line A549 cells
Human U2OS cells
caspases 8, 9, 3, 7 , ROS, bax, p53, p21,
Lung cancer cells
Deoxyelephantopin
Costunolide
TIMP-2, activated p-JNK, p-p38, NF-κB and IκBα expressions
UM-SCC-10A cell line
Isoalantolactone
Bax, Cyt-c, JNK, caspase-3 and caspase-9, reactive oxygen species (ROS) generation and ER stress-induced mitochondrial dysfunction GRP78,IRE1α,, ASK1, JNK, ROS generation,
p53, p21, Bax, mitochondrial release of cytochrome c , activation of caspase-3 ,
MMP-2, MMP -9,
SW-872 (human liposarcoma), SW-982 (human synovial sarcoma) and TE-671 (human rhabdomyosarcoma)
Costunolide and dehydrocostus lactone
GSH depletion, inhibition of STAT3 activation, Bax generation ROS, Bax caspases-8, caspases -9, caspases -3, PARP, Bax Generation ROS, P53, Bax
HepG2 Cell Human cervical cancer cell Lung Squamous Cancer SK-MES-1 Cell glioblastoma cells
Alantolactone
Increse
Parthenolide
Effect on cancer cells
Type of cancer cells
Name Compounds
Table 1 Summary of the effects sesquiterpene lactones on the factors involved in cancer.
[58]
Bcl-2
[59]
[57]
[56]
[55]
[54]
[51] [52] [53] [23]
[49,50]
[47] [48]
MMP-2, MMP-9, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, p-ERK1/2 and p-Akt, Bcl2, Bcl-Xl, pSTAT3, cdc2, cyclin B1, p-Akt, p-mTOR,
cyclin D, Bcl-2, reduction of mitochondrial membrane potential,
cyclin B1, CDK1, CDK2,
ROS generation Bcl-2, caspase-3 activation GSH, Bcl-2 Bcl-2, CDK4, CDK6, cyclin D3, cyclin D1 GSH, Bcl2, cytochrome, Activation of caspases 3, caspases 9, poly ADP-ribose polymerase
Bcl-2 VEGF, decreased nuclear localization of NF-kB and phosphorylated NF- kB protein, MMP-9, Bcl-xL, Cox-2 Bcl-2 NF-κB
Decrease
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causing the growth, proliferation and metastasis of cancer cells [21]. Moreover, studies on EM23 indicate that this substance inhibits the expression of thioredoxin and thioredoxin reductase and disrupts the balance of redox cells. On the other hand, the reduction of thyroxine activates ASK1, and this activates the downstream ASK1 factors, namely, p38, JNK and ERK MAPKs, resulting in the induction of apoptosis. This compound also inhibits the activity of NF-kB activated by TNF-α [22]. Dimethylaminopartenolide (DMAPT) has been recently evaluated as one of the compounds of the sesquiterpene lactones in clinical trials in Phase 1 for solid tumors [9]; it causes anticancer effects with various mechanisms including ROS generation, gene expression change through epigenetics, the targeting of the sarcoplasmic reticulum Ca2+ ATPases (SERCA), NF-kB and p53 signaling pathways, angiogenesis and metastasis [23]. Based on a study conducted on three cell lines; NIH 3T3, MCF-7 and Hela, the anticancer effects of sesquiterpenes have been strongly confirmed through the signaling pathways of NF-kB and p53 [24]. Recent studies have shown that sesquiterpene lactones cause changes in cell redox balance and oxidative stress in cells (Fig. 4). Oxidative stress involves the accumulation of free radicals oxygen inside, which can lead to the spread of cancer. On the other hand, increased free radicals can induce apoptosis through mitochondrial effects. Glutathione (GSH) is one of the antioxidant factors, having a high concentration in cancerous cells compared to normal cells. Recent studies on parthenolide sesquiterpene lactones have shown that this compound increases the free radicals through the inhibition of NF-kB, signal transducer and activator of transcription 3 (STAT3) and also P53. Parthenolide inhibits the decomposition of this inhibitory protein through the binding to the IkB-α subunit acting as an NF-kB inhibitor. Conversely, studies show that, in the normal state, the inner surface of the cell is restored compared to the external part, but in cancer cells, this state is reversed and the outer region is restored more than the internal part. In this situation, the presence of the extracellular thiol group can be a suitable factor for the selective action of parthenolide sesquiterpene lactones [25]. Matsuda et al. reported the isolation and characterization of active component from the leaves of L. nobilis, structure-activity relation of active component of the plant, the description of the effects of costunolide and dehydrocostus lactone which possessed a higher potency
Their investigation suggest that the sulfur of Nuphar dimers is capable of reacting as an electrophile in cell environments and sulphur can activate cells retrodimerization. Furthermore, Jansen et al. reported the synthesis of asymmetric dimeric thiaspirane nuphar alkaloid from 3-methyl-2-cyclopentenone through eight step process. This route of synthesis is dependent upon a useful method for tandem reductive cyclopentenones allylation, redox manipulation minimization and interconversions of other functional groups. The catalytic asymmetric method to the nuphar quinolizidine family is yet to be fully explored [17]. 4. Anticancer properties of sesquiterpene lactones Sesquiterpene lactones are one of the important nucleus in medicinal plants. However, recent anticancer activities of different types of sesquiterpene lactones (Table 1) have attracted the attention of many researchers. Extensive research has been carried out to express the anticancer activity, molecular mechanism, and chemotherapeutic and chemoprotective potential of these compounds [19]. Inhibition of the signaling pathway of Nuclear Factor-kB (NF-kB) is one of the mechanisms by which sesquiterpene lactones produce their anticancer effects (Fig. 3). NF-kB in cancer cells has a major role in inhibiting apoptosis, induction of metastasis, cell proliferation, cell transformation, invasion, metastasis, resistance to chemotherapy, and resistance to radiotherapy [5]. Studies have shown that one of the common goals of sesquiterpene lactones is to inhibit the NF-kB pathway. This factor is made up of two subunits; p50 and p65 in the normal state, which is inhibited by cytoplasmic inhibitor of kB (IkB). At the time of stimulation of the cells by cytokines, the Protein kinase IKKβ [9] is activated, causing phosphorylation and ubiquitinization of IkB, and, eventually, degradation by the proteasome complex. As a result, inhibition was removed from NF-kB, and dimers of p50 and p65 enter the nucleus and increase the expression of target genes [20]. Dihydrocastenolide is a sesquiterpene lactone that applies its anticancer effects through the NFkB pathway. This compound inhibits the IKKβ kinase, which seems to be done by connecting to the ATP binding site, inhibiting NF-kB and the use of p300, thereby leading to the accumulation of these factors in the cytoplasm. Consequently, the level of COX-2 expression decreases in melanoma cancer. This factor is greatly enhanced in melanoma cancers,
Fig. 3. The Sesquiterpene lactone is largely affected by two path ways. The result of inhibition of these two pathways by using lactogenic sesquiterpenes can inhibit cancer cells. 242
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Fig. 4. Mechanism of antioxidant effect of sesquiterpene lactone.
deoxyelephantopin (DET) had anti-tumorigenic effect and if they can upregulate pro-inflammation of NF-κB in tumor cells? Several breast cancer cells such as MDA-MB-231, MDA-MB-453, MDA-MB-468, MCF7, and C6-glioma cell lines were used. IDET was found to inhibit the growth of different glioma and breast cancer cell lines in a time and dose dependent manner. IDET was more potent compared to DET. The sesquiterpene stimulated apoptosis in tumor cell and suppressed the expression of tumor cell survival. De Ford et al. [28] results showed that sesquiterpene lactones from S. sonchifolius have an outstanding cytotoxicity, most especially polymatin B and fluctuanin and may probably be therapeutically be synthesized to make useful drugs. However, more investigations is suggested to gain more insights in the mechanism of necroptosis and apoptosis and particularly their potency has to be confirmed in vivo. Another study showed that alantolactone act as an anticancer agent by inhibiting the thioredoxin reductase enzyme. This compound increases the oxidized form of this enzyme by thioredoxin reductase inhibition, and also induces apoptosis in HeLa cells by increasing the amount of free radicals oxygen [29]. A recent study has also shown that the parthenolide and its water-soluble form, DMAPT, increase the production of hydrogen peroxide by activating the NADPH oxidases (NOXs) in Triple-negative breast cancer (TNBCs) cells in the early hours after treatment with these compounds. These two substances also reduce the expression of the factor Nrf2, which is an essential in the production of antioxidant proteins. Long-term treatment with this substance (12–24 h) increases the level of superoxide anions and highly reactive oxygen species, while decreasing superoxide dismutase (SOD) and catalase (CAT) at the same time [30]. In a study, Ozer et al. [18] screened thirty-four methanolic plant extracts for the downregulation of NFkappaB activity using a NFkappaB-luciferase reporter gene assay. They observed that the downregulation of NFkappaB activity was found in the extracts of rhizome and leaf of Nuphar, which was traced to a mixture of thionupharidines and/or thionuphlutidines (dimeric sesquiterpene thioalkaloids). Their findings showed that NUP downregulates the NFkappaB pathway acting as a sensitizer to traditional chemotherapy, this lead to the growing interest of this active compound for the treatment of cancer. Matsuda et al. [31] isolated four monomeric sesquiterpene alkaloids and seven dimeric sesquiterpene thioalkaloids from N. pumilum rhizomes using methanol. The extract obtained decreases B16 melanoma cells invasion across collagen-coated filters. The thiohemiaminal
Fig. 5. Structures of different sesquiterpene lactones compounds referred to in the text [7].
than other sesquiterpenes, on iNOS and heat shock protein (HSP) 72 activation, sesquiterpene lactones from bay leaf showed potent downregulation effects on NO synthesis in LPS-activated macrophages [26] (Fig. 5). Ichikawa et al. [27] examined if isodeoxyelephantopin (IDET) and 243
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continuation of the cell cycle in the S phase and stimulating apoptosis by inhibiting the function of STAT3 and NF-kB. Thus, alantolactone inhibit the activity of NF-kB by inhibiting p65 and TNF-α and IL-6 induction on STAT3. Moreover, the inhibition of the STAT3 phosphorylation and the inhibition of the function of its target genes are similar to survivin [44]. On the other hand, these compounds can produce antitumor properties through changes affecting the epigenetic process. One of the characteristics of various tumors is the 5′-CpG islands of hypermethylation. The hypermethylation of tumor suppressor genes causes these genes to be mutated, which leads to cancer. Studies have shown that the parthenolide reduce the amount of methylation by inhibiting the catalytic domain DNMT1 enzyme and decreasing activity of this enzyme, which acts as an inhibitor of hypermethylation [45]. Histone deacetylases are a group of enzymes that play a major role in epigenetic changes in chromatin, inhibitors of this enzyme are one of the promising therapies. The inhibitors of this enzyme affect the histone deacetylases due to non-specific activity. Parthenolide is a novel inhibitor compound that specifically inhibits HDAC1, but has no effect on classes 2 and 3 of histone deacetylases [46]. The plants of the genus Inula (Asteraceae) are distributed across Africa, Asia, Europe, and most of these plants have long been employed in folk medicine. This plant genus is highly rich in sesquiterpenoids. Cytotoxic and anticancer properties of Inula sesquiterpenoids have been studied extensively since 1970s. A potential compound, Japonicone A, which is a dimeric sesquiterpene lactone from traditional herb Inula japonica, has demonstrated potent in vitro and in vivo anti-tumor activity against Burkitt's lymphoma. Apoptosis induction in cancer cells is a potential method of treatment in tumor therapy. Hamzeloo-Moghadam et al. [60] showed that britannin, a sesquiterpene lactone, possesses antiproliferative activity on the MDA-MB-468 and MCF-7 human breast tumor cells. Hoechst 33,258 staining, Annexin V/propidium iodide (PI) staining, and caspase-3/9 activity assay showed that britannin is capable of inducing apoptosis in the two cell lines. Analysis by western blot showed that bcl2 expression was downregulated significantly in response to treatment by britannin, whereas Bax protein was upregulated, which corresponds with p53 upregulation. In addition, britannin also stimulated reactive oxygen species (ROS) build-up which in turn activated the loss of mitochondrial transmembrane potential (ΔΨm) and subsequently cytochrome c was released from the mitochondria into the cytosol. Collectively, these results proposed that britannin hinders the growth of MDA-MB-468 and MCF-7 breast cancer cells via mitochondrial apoptotic pathway activation and may potentially finds application as an active ingredient in breast cancer therapy. Bosco et al. [61] listed the sesquiterpenes that attack cells in mitosis assessing biological data that assist those observations. Considering mitosis biochemical complexity, they proposed that sesquiterpenes subsets possess a distinct chemical structure capable of targeting a precise protein(s) required for mitosis, this gives a new perspective of sesquiterpene chemical biology.
structure with the 6-hydroxy group in thioalkaloids is crucial for potent activity. The alkaloid constituent as well as the main dimeric sesquiterpene thioalkaloid significantly inhibited the formation of lung cancer [31]. In another separate study, Ozer et al. [32] assessed the effect of leaf and rhizome extracts (NUP) in a B16 melanoma experimental murine lung metastasis model and its potential to affect the NF-κB and ERK pathways in several cell lines. They observed that NUP and standard anticancer drug (cisplatin) combination therapy was synergistic and decreases the load of lung metastatic. Furthermore, the treatment with NUP downregulated TNFα-induced IκBα degradation, so as NF- κB nuclear translocation. NUP induced ERK upregulation was also observed, and its downregulation prevented NF-κB inactivation by NUP. 5. Mechanism of antioxidant properties elucidation by sesquiterpenes Recently, studies on non-small lung cancer (NSCLC) cell lines (A549 and H522) and the immortalized human bronchial epithelial cell line (BEAS2B), transitional cell cancer (TCC) cell lines (UMUC-3, HT-1197 and HT-1376), and bladder papilloma (RT-4) have shown that DMAPT inhibits the connection of NF-kB to DNA and also activates JNK. This condition reduces anti-apoptotic, TRAF-2, and XIAP proteins, increases the amount of p21 and p73 proteins, and cyclin D1 inhibition, ultimately inhibiting the cell cycle and inducing apoptosis [33]. STAT3 is another factor that is controlled by the sesquiterpene lactones. This factor is abnormal in many cancers and has a tumorigenic effect. In cancer cells, this compound leads to apoptosis inhibition, metastasis induction, cell proliferation, cellular invasion, and eventually tumor progression [34]. Alantolactone is one of the sesquiterpene lactones that specifically inhibit STAT3 activity. The possible binding to the SH2 domain of STAT3, inhibits the activity of this transcription factor. It also inhibits translocation to the nucleus and bind to specific DNA- response elements in target gene promoters. It, thus, inhibits the expression of target genes, such as cyclin D1, COX-2, c-myc, mmp-9 and CXCR4, resulting in cell invasion in the G2/M phase and inhibition of metastasis and cellular invasion [35]. However, recently, a mechanism has been proposed for inhibiting STAT3. Cynaropicrin, a sesquiterpene lactone increase free radicals by changing the balance of [GSH]/[GSSG]. The [GSH]/[GSSG] imbalance in cells causes S-glutathionylation of amino acids in many sensitive proteins [36]. One of these proteins is STAT3, which results in STAT3 S-glutathionylation. These post-translational modification cause interference in STAT3 phosphorylation and the inhibition of activation of this transcription factor, the expression of bcl2, and survivin, and ultimately the induction of apoptosis [36]. Such post-translational modification and STAT3 inhibition have been also observed for dehydrocostus lactone and costunolide [37]. One of the reasons for the inhibition of the STAT3 binding to its binding site on the related DNA is probably the oxidation of the amino acid cysteine associated with the binding domain to the DNA by free radicals produced by sesquiterpene lactones [38]. Recent studies have shown that sesquiterpene lactones, the natural substance of tetrahydrofuran-2 pyran have anticancer effects in various human cancers: in colon cancer (HCRC) they activate both apoptosis pathways that are dependent on and independent of caspase [39]; in cervical cancer, they decrease the expression of bcl-2 and increase the expression of p53 [40]; in HL-60 cell leukemia, activate and induce apoptosis through oxidative stress [41]; in bladder cancer of the T24 cell line, activate MAPK-p38 and inhibit the Akt pathway, causing a loss of balance in the mitochondrial membrane [42]; in breast cancer; mutations in HER2 and its receptors. There are several signaling pathways for the incidence of cancer, such as the PI3K/PTEN/Akt/mTOR, and the Ras/Raf/Mek/Erk signaling pathways. Altolactone can inhibit tumorigenicity and tumor progression by inhibiting the PI3K/PTEN/Akt/mTOR pathways [43], and, in prostate cancer, by inhibiting cell proliferation and preventing the
6. Conclusion Sesquiterpene lactones elicit an anticancer effects through a changes in the redox cell balance and their impact on various signaling pathways, especially the NF-kB pathway and STAT3. These activities lead to the reduction in the expression of factors involved in cell cycles, the increase in apoptotic factors, and the reduction of anti-apoptotic, metastasis, and cellular invasion factors. On the other hand, the production of free radicals induces apoptosis and has effects on the pathways mentioned in various cells. The nucleus of sesquiterpene lactones is essential for the development of a novel active terpenoids which may be helpful for cancer therapy.
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Declaration of interest
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