Chapter 20

Chalcones Target the Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) Signaling Pathway for Cancer Chemoprevention

Małgorzata Kłósek1, Andrzej Karol Kuropatnicki2, Ewelina Szliszka1, Ilona Korzonek-Szlacheta1 and Wojciech Król1,    1Medical University of Silesia, Katowice, Poland,    2Pedagogical University of Krakow, Krakow, Poland

Abstract

Chalcones belong to the flavonoids family and are natural compounds present in edible plants. The term chalcone was coined by Stanisław Kostanecki and Josef Tambor. Chalcones exhibit a broad spectrum of biological activity and thus have attracted more and more attention due to their anticancer and chemopreventive effects. Chemoprevention is one of the most promising approaches for arresting many types of cancer cells or reversing the process of carcinogenesis. Preclinical and epidemiological studies have shown that chalcones can inhibit cancerogenesis at very early stages. The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a protein that exists in soluble form or is expressed on the surface of immune effector cells. This ligand induces apoptosis in cancer cells while showing no toxicity for normal cells. Some cancer cells, however, are resistant to TRAIL-mediated cell death through a many survival mechanisms. Chalcones in combination with TRAIL can sensitize TRAIL-resistant cancer cells to apoptosis through different mechanisms in apoptotic pathway.

Keywords

Chalcone; chalcone synthesis; TRAIL; chemoprevention; cancer cell

Introduction

Chalcones are natural biocides and considered as intermediate in the biosynthesis of flavonoids. They are commonly found in edible plants. Their name derives from a Greek word χαλκentς meaning copper or brass (Nickon and Silversmith, 1987). Chalcones and their derivatives constitute an interesting class of compounds due to their synthetic versatility. They have been shown to possess numerous effective biological activities such as antiinflammatory, anticancer, antihypertensive, antibacterial, antiretroviral, antimalarial, antioxidant, antifungal, antispasmodic, antiparasitic, antidiabetic, antihistamine, antiangiogenic, antiarrhythmic, antinociceptive, antiplasmodial, and antiobesity as well as hypnotic, cardioprotective, immunosuppressant, and cytotoxic (Singh et al., 2014).

The first dihydrochalcone, phlorizin (phloridzin), a naturally occurring flavonoid, was initially described by Philipp Lorentz Geiger in 1834. The German pharmacist and professor of pharmacy at the University of Heidelberg isolated it from apple root bark. One year later, in 1835, Laurent-Guillaume de Koninck, a Belgian chemist, characterized phlorizin and named it using the Greek words φλentος for “bark” and ententζα for “root” (Definitions.net “phlorizin”; Koninck et al., 1835). Phlorizin occurs in minute and slightly pinkish crystals and is sparingly soluble in cold water, alcohol, and ether (Krotoszyner and Stevens, 1917). The first chalcone described as a naturally occurring compound was carthamine, a natural red pigment from safflower (Carthamus tinctorius), a dye plant used in India (Bhardwaj and Jain, 1982). Carthamine was used as a dye not only in ancient times (Candolle, 1885) but also later in the European wool-dyeing industry as well as in Japan for making cosmetics for use by geishas and kabuki artists (Definitions.net “carthamin”).

Stanisław Kostanecki, a Polish organic chemist who worked at the University in Bern, Switzerland, pioneered in vegetable dye chemistry. In 1893, he found out that the phenol derivative of benzopirene is a matrix substance of chrysine, which was named by him flavonoid after Latin term flavus for yellow (Kuropatnicki et al., 2014). Kostanecki together with Josef Tambor was the first who coined the term chalcone (Kostanecki and Tambor, 1899). In 1925, H. F. Dean and M. Nierenstein described the isomeric relationship involving the ring opening of flavanones to yield chalcones (Dean and Nierenstein, 1925).

Polyphenols are secondary plant metabolites present especially in fruit, vegetables, spices, green tea, olive oil, red wine, and beer—they have become integral parts of the human diet. More than 8000 different phenolic compounds have been identified in the plant kingdom (Dai and Mumper, 2010; Pietta, 2000) and can be divided into flavonoids, phenolic acids, stilbenes, and lignans (Pandey and Rizvi, 2009). Flavonoids are further subdivided into nine classes, including flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, isoflavones, proanthocyanidins, aurones, and chalcones (Mahapatra et al., 2015). The basic chemical structure of flavonoids is the flavan backbone in which two phenolic rings, A and B, are linked by a heterocyclic ring, C (Busch et al., 2015; Pietta, 2000; Vue et al., 2015).

Chalcones, an important group of the flavonoids, have interesting biological properties. So far, they have received increasing attention due to their potent antioxidant properties and anticancer effects (Orlikova et al., 2011). Much attention has been given to chemoprevention as an alternative approach to cancer control.

Cancer development is a multistage process that starts with initial mutations that are followed by promotion and progression and ultimately some form of malignancy. At the beginning of the 21st century, cancer was the second leading cause of death after heart disease in the European Union and the United States (Kang et al., 2011). Chemoprevention is one of the most promising approaches used against many cancer cells to arrest or reverse the process of carcinogenesis through dietary compounds or synthetic pharmacological agents or both (Sporn et al., 1976). In the last 20 years, numerous preclinical and epidemiological studies have shown that natural dietary products play role in the prevention of cancers (Sirerol et al., 2016).

Chalcones can inhibit cancerogenesis from the its earliest stages, including tumor initiation, promotion, and progression. One important event for cancer chemoprevention is the induction of apoptosis. In some cancer cells, one pathway—the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)—mediates apoptosis by making tumors attractive targets for the chemopreventive activities of specific dietary agents. Chalcones can target the TRAIL-induced apoptotic pathway and sensitize cancer cells. However, some tumor cells are resistant to apoptosis as mediated by TRAIL. New strategies to overcome this resistance are critically important to cancer chemoprevention. This chapter shows the mechanisms of sensitization of TRAIL resistance cancer cells by chalcones.

Characteristics of TRAIL and Apoptosis Induced by TRAIL

TRAIL is a 20-kilodalton protein encoded by a gene located on chromosome 3. It was discovered by two independent groups as a novel pro-apoptotic member of the tumor necrosis factor superfamily with the highest homology to CD95L (FasL/APO-1L) (Pitti et al., 1996; Wiley et al., 1995). TRAIL is a type II transmembrane protein but can be cleaved by metalloproteases to yield a soluble form (Secchiero et al., 2010). This ligand is expressed on the surface of immune effector cells such as dendritic cells, macrophages, natural killer cells, and cytotoxic T cells (Holoch and Griffith, 2009). It has the ability to selectively induce apoptosis in cancer cells without having toxic effects for normal cells. Several TRAIL receptors have been discovered to date, including TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), and soluble osteoprotegerin (OPG) (Emery et al., 1998; MacFarlane et al., 1997). TRAIL-R1 and TRAIL-R2 are called death receptors because they have ability to transduce signals to apoptosis (Mahmood and Shukla, 2010). TRAIL-R3 and TRAIL-4 are called decoy receptors because they lack a functional death domain and are unable to activate apoptotic signaling. TRAIL-R3 lacks an intracellular domain and has a glycosylphosphatidylinositol membrane anchor instead. TRAIL-R4 has a truncated death domain and is missing 52 of the 76 amino acids found in the death domains (DDs) of death receptors (Amarante-Mendes and Griffith, 2015). OPGs may also function as decoy receptors, although their relevance is unclear (Amarante-Mendes and Griffith, 2015; Emery et al., 1998). The physiological role of osteoprotegerin is to inhibit the RANKL–RANK interaction in bone morphogenesis (Boyce and Xing, 2007). The types of TRAIL receptors are shown in Fig. 20.1.

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Figure 20.1 TRAIL receptors and the ability to induce apoptosis mediated by TRAIL.

Two pathways of TRAIL-induced apoptosis have been identified: the extrinsic (receptor-mediated) and the intrinsic (mitochondrial) (Fig. 20.2) (MacFarlane, 2003; Sayers, 2011). TRAIL induces apoptosis in cancer cells via a receptor-mediated pathway. It binds to the death receptor TRAIL-R1 (DR4) or TRAIL-R2 (DR5) (or both) and leads to the trimerization of receptors. This results in the recruitment of the adaptor molecule, Fas-associated death domain (FADD), to form the death-inducing signaling complex (DISC) (Pennarun et al., 2010). The death effectors domain (DED) of Fas-associated protein has been recognized by the DED of caspase-8, leading to its autoactivation. In type I cells, activation of caspase-8 is sufficient for subsequent activation of effector caspase-3 or caspase-7, leading to apoptosis. In type II cells, signal amplification via the intrinsic pathway is necessary for apoptosis (Ozören and El-Deiry, 2002). In this type of cell, caspase-8 cleaves Bid to truncated Bid (tBid), which migrates to the mitochondrial membrane and stimulates the oligomerization of Bak and Bax to form pores in the outer mitochondrial membrane. This allows for the release of mitochondria proteins such as cytochrome c, apoptosis-inducing factor, and Smac/DIABLO into the cytosol. Cytochrome c binds apoptotic peptidase activating factor 1 (Apaf-1), dATP, and caspase-9 to form apoptosome. Caspase-9 is activated and cleaves caspase-3 to initiate apoptosis (Holland, 2013; Mellier et al., 2010; Russo et al., 2010; Schulze-Osthoff et al., 1998).

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Figure 20.2 The pathways of TRAIL-induced apoptosis and molecular targets of chalcones. Bluemarks TRAIL’s receptors, yellow arrowheads mark activation, and red arrowheads mark inhibition.

Some cancer cells are resistant to TRAIL-mediated cell death through a variety of survival mechanisms. One reason is deletion in TRAIL-R1 observed in nasopharyngeal cancer and mutations in TRAIL-R2 in breast cancer, lung cancer, and head and neck cancer (Lim et al., 2015; Zhang and Fang, 2005). In turn, a lack of expression of TRAIL-R1 due to epigenetic silencing has been observed in ovarian cancer cells (Horak et al., 2005a). On the other hand, high mRNA expression of DcR1 and DcR2 found in human osteoblast cells also correlates with resistance to TRAIL-mediated apoptosis (Lim et al., 2015). High levels of c-FLIP that inhibit activation of caspase-8 at the DISC have been correlated with resistance to TRAIL observed in several cancer types, including lung and breast cancers, colon cancers, ovarian cancers, and B-cell chronic lymphocytic leukemia (Guseva et al., 2008; Horak et al., 2005b; Wang et al., 2008). Overexpression of antiapoptotic proteins Bcl-2 in breast cancer cells and Bcl-xL in pancreatic cancer cells have reportedly resulted in TRAIL resistance (Fulda et al., 2002; Hinz et al., 2000). High levels of antiapoptotic proteins XIAP, cIAP-1, cIAP-2, and survivins lead to TRAIL resistance in prostate cancer cells (McEleny et al., 2002). High XIAP expression has been postulated as a mechanism of resistance to TRAIL in colon cancer and pancreatic cancer (Li et al., 2013; Ndozangue-Touriguine et al., 2008; Ozören and El-Deiry, 2002). Mutation in the pro-apoptotic protein Bax has been shown to contribute to TRAIL resistance in human colon carcinoma cells (LeBlanc et al., 2002). Understanding mechanisms of TRAIL resistance in cancer cells can help researchers find more suitable strategies to overcome TRAIL resistance and obtain better therapeutic outcomes.

Characteristics of Chalcones

Chalcones or 1,3-diaryl-2-propen-1-ones are a group of polyphenolic compounds belonging to the flavonoids family. They are the precursors of flavonoids and isoflavonoids (Sahu et al., 2012). Chemically, they consist of open-chain flavonoids in which the two aromatic rings are joined together by three carbons in an α,-unsaturated system (Nowakowska, 2007) (Fig. 20.3).

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Figure 20.3 The core of chalcone structure.

The structure of chalcones is diverse due to the number and position of various substituents, including hydroxy or methoxy groups on the A or B rings. Chalcones are also C-prenylated and. more rarely, O-prenylated. The most frequent type of prenylation is 3,3-dimethylallyl substitution (prenyl group). Besides this, they also have isopentenyl, furano, dimethylchromano, geranyl, and farnesyl groups (Zsuzsanna Rozmer, 2014). Most prenylated chalcones have been isolated from the Moraceae (broussochalcone A) and Leguminosae families, and several compounds were isolated from Humulus lupulus (xanthohumol, desmethylxanthohumol) (Botta et al., 2005; Zsuzsanna Rozmer, 2014). Dihydrochalcones belong to a small group of flavonoids in which a three-carbon bridge double bond has been reduced as in asebogenin or phloridzin.

The chromone—1-benzopyran-4-one—is the core in several flavonoids. One of the first methods for synthesizing chromones was introduced by the aforementioned Stanisław Kostanecki; hence, this reaction is now known as the Kostanecki acylation. Chalcones are synthesized by Claisen-Schmidt condensation of an aromatic aldehyde and ketone in a polar solvent. Chalcones can easily be cyclized to flavanones by a Michael addition at the β position of the carbonyl (Claisen and Claparède, 1881; Orlikova et al., 2011; Zhang et al., 2013). Reaction of 2ʹ-hydroxyacetophenone with benzaldehyde in the 0.1 M NaOH gives 2ʹ-hydroksychalcone (Fig. 20.4) (Avupati and Yejella, 2014).

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Figure 20.4 Synthesis of 2ʹ-hydroksychalcone in Claisen-Schmidt condensation between 2ʹ-hydroxyacetophenone and benzaldehyde.

Condensation between acetophenone and benzaldehyde by sonochemical and thermally activated reactions over a zeolite as catalyst to give chalcone is presented in Fig. 20.5 (Avupati and Yejella, 2014).

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Figure 20.5 Synthesis of chalcone in Claisen-Schmidt condensation between acetophenone and benzaldehyde.

Other methods for obtaining chalcone use Suzuki, Friedel-Crafts, or Julia-Kocienski reactions. Synthesis of chalcones in a Suzuki reaction occurs between activated cinnamic acids and phenylboronic acids (Fig. 20.6) or between activated benzoic acids and phenylvinylboronic acids (Eddarir et al., 2003).

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Figure 20.6 Synthesis of chalcone in Suzuki reaction between phenylvinylboronic acids and cinnamic acids.

A different method of chalcones synthesis is the reaction of arylboronic acids with benzoic anhydride in the presence of PdCl2 and Na2CO3 in H2O/acetone (Fig. 20.7) (Selepe and Van Heerden, 2013).

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Figure 20.7 Synthesis of chalcone between benzoic anhydride and arylboronic acids.

The biosynthesis of chalcones in plants is initiated by chalcone synthase, which leads to condensation of three acetate units starting from malonyl-CoA with p-coumaroyl-CoA to 4,2ʹ,4ʹ,6ʹ-tetrahydroxychalcone, also known as naringenin chalcone (Fig. 20.8) (Schijlen et al., 2004).

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Figure 20.8 Synthesis of chalcone in plants.

Many plants do not accumulate chalcones, and this reaction is the first step in the synthesis of the remaining class of flavonoids such as flavanones, dihydroflavonols, and anthocyanins. In turn, isoflavones, flavones, flavonols, aurones, or proanthocyanidins represent side branches of the flavonoid pathway. Chalcones can be found in many plants (Table 20.1).

Table 20.1

Examples of chalcones naturally occurring in plants

Chalcone Major Sources References
Asebogenin (dihydrochalcone) Piper aduncum leaves, Piper longicaudatum, Pieris japonica leaves Joshi et al., 2001; Orjala et al., 1994; Yao et al., 2005
Aurentiacin Syzygium samarangense Kim et al., 2012
Broussochalcone A (prenylated chalcone) Broussonetia papyrifera Sohn et al., 2004
Butein Stembark of cashews, Semecarpus anacardium, the heartwood of Dalbergia odorifera, traditional Chinese and Tibetan medicinal herbs, Caragana jubata, and Rhus verniciflua Stokes Cheng et al., 1998; Yadav et al., 2011
Cardamonin Herbal tea Catimbium speciosum, pulp and seeds of the fruits of Syzygium samarangense Ohtsuki et al., 2009; Simirgiotis et al., 2008
Derricin Lonchocarpus neuroscapha Gonçalves de Lima et al., 1975
Desmethylxanthohumol (prenylated chalcone) Female flowers of hops (Humulus lupulus) De Keukeleire et al., 2003
Flawokawain B Piper methysticum (Kava) Lebot et al., 2014; Tang et al., 2010
Flavokawain C Piper methysticum (Kava) Tang et al., 2010
Isobavachalcone (prenylated chalcone) Psoralea corylifolia, Psoralea longum, Angelica keiskei, Maclura tinctoria ElSohly et al., 2001; Yan et al., 2015
Isocordoin Aeschynomene fascicularis Caamal-Fuentes et al., 2015
Isoliquiritin Glycyrrhiza sp. Wu and Meng, et al., 2013
Isoliquiritigenin Dalbergia odorifera, roots of Glycyrrhiza uralensis, Glycyrrhiza glabra, Mongolian glycyrrhiza Li et al., 2010; Peng et al., 2015; Zhao et al., 2011
Licochalcone A Root of Glycyrrhiza inflata, Glycyrrhiza glabra Fu et al., 2004; Furusawa et al., 2009
Licochalcone E Roots of Glycyrrhiza inflata Kwon et al., 2013
Millepachine Millettia pachycarpa Wu and Ye, et al., 2013
Myrigalone B Myrica gale Mathiesen et al., 1997
Panduratin A Kaempferia pandurata Lee et al., 2010
Phloretin (dihydrochalcone) Leaves of Malus (crabapple), leaves of Pieris japonica Qin et al., 2015; Yao et al., 2005
Phlorizin (phloridzin) (dihydrochalcone) leaves of Malus (crabapple), leaves of Pieris japonica Qin et al., 2015; Yao et al., 2005
Pinocembrin chalcone Helichrysum trilineatum Bremner and Meyer, 1998
Stercurensin Pulp and seeds of fruits of Syzygium samarangense Simirgiotis et al., 2008
Viscolin Viscum coloratum Hwang et al., 2006
Xanthoangelol (prenylated chalcone) Angelica keiskei Ohnogi et al., 2012; Tabata et al., 2005
Xanthohumol (prenylated chalcone) Female flowers of hops (Humulus lupulus) Lee et al., 2012; Liu et al., 2014

Chalcones represent an important class of natural flavonoids useful in medicine and pharmacology. Many patents describe the isolation of chalcones from plant extracts and use them as additives in cosmetics and other preparations. Isoliquiritigenin used in the treatment and prevention of cardiovascular diseases was patented for the prevention of skin aging by cosmetics companies. Licochalcone A was patented as cosmetic toner, antiacne, and skin-whitening agent. Isobavachalcone was patented as an agent for treating inflammatory nerve diseases (Matos et al., 2015). As previously mentioned, chalcones have a broad spectrum of biological properties such as antioxidant, antimicrobial, and antiinflammatory activities (Sahu et al., 2012). Over the past 10 years, about 90 compounds of chalcones with antitumor activities have been found (Zhang et al., 2013). Chalcones show cytotoxicity against a wide range of cancer cell lines, including prostate cancer, breast cancer, leukemia, hepatoma, stomach cancer, and colorectal cancer. The IC50 values of the majority of compounds were found to be below 50 μM (Zhang et al., 2013). Calcones induce apoptosis in cancer cells through a death receptor–mediated pathway, a mitochondrial-mediated pathway, or a nuclear factor kappa B pathway.

Chalcone Potential for Enhancing TRAIL-Mediated Apoptosis in Cancer Cells

TRAIL resistance in some cancer cells can be overcome by flavonoids. The preclinical studies have shown that chalcones in combination with TRAIL can sensitize TRAIL-resistant cancer cells to apoptosis induced by TRAIL. Chalcones such as butein, cardamonin, chalcone, xanthohumol, isobavachalcone, isoliquiritigenin, licochalcone A, and flavokawain B augment anticancer activities through different mechanisms in the apoptotic pathway. The molecular targets for chalcones in many cancer cells are presented in Table 20.2 and Fig. 20.2.

Table 20.2

Examples of chalcones that enhance TRAIL-induced apoptosis in cancer cells

Naturally Occurring Chalcone Chemical Structure Targets Cell Lines References
Butein image Increase: DR5, caspase-3, caspase-8, caspase-9, PARP, cytochrome c release; activation Bid to tBid Decrease: Bcl-2, XIAP, IAP-1, IAP-2 Prostate cancer LNCaP, prostate cancer PC3,Leukemia U937, leukemia Jurkat, leukemia K562, hepatocellular cancer Hep3B and HepG2, colon cancer HCT116 Kim, 2008; Moon et al., 2010; Szliszka et al., 2009
Cardamonin image Increase: DR4, DR5, caspase-3, caspase-8, caspase-9 Decrease: Bcl-xL Colon cancer DLD-1, colon cancer HCT116, gastric carcinoma AGS, leukemia KMB-5, ultiple myeloma U266, pancreatic cancer MiaPaCa, prostate cancer DU145, prostate cancer PC3 Kim et al., 2012; Ohtsuki et al., 2009; Yadav et al., 2012
Chalcone image Increase: DR5 Prostate cancer LNCaP, cervical cancer HeLa Szliszka et al., 2010; Szliszka et al., 2009; Szliszka et al., 2012
Xanthohumol image Increase: DR5 Prostate cancer LNCaP, cervical cancer HeLa Szliszka et al., 2009; Szliszka et al., 2012
Isobavachalcone image Increase: DR5 Prostate cancer LNCaP, cervical cancer HeLa Szliszka et al., 2009; Szliszka et al., 2012
Isoliquiritigenin image Increase: DR5, caspase-3, caspase-8, caspase-9, caspase-10 Colon cancer HT29 Yoshida et al., 2008
Licochalcone A image Increase: DR5 Prostate cancer LNCaP, cervical cancer HeLa Szliszka et al., 2009; Szliszka et al., 2012
Flavokawain B image Increase: DR5, caspase-3, caspase-8, caspase-9, Bax, Bim, Puma Decrease: XIAP, survivin Prostate cancer PC-3 Tang et al., 2010

Image

Butein is a 3,4,2ʹ,4ʹ-tetrahydroxychalcone isolated from Toxicodendron vernicifluum (Rhus verniciflua), Butea monosperma, Semecarpus anacardium, or Dalbergia odorifera (Padmavathi et al., 2015). Szliszka et al. have shown that butein at concentrations of 20 and 50 μM in combination with TRAIL at concentrations of 20–100 ng/mL increased the percentage of cell death in LNCaP prostate cancer cells from 36.82 ±0.87% to 81.97 ±0.84% (Szliszka et al., 2009). Leukemia cell lines U937, Jurkat, and K562 were pretreated with butein for 12 h at concentrations of 5 and 7.5 µg/mL and further incubated with TRAIL for 24 hours at concentrations of 50–200 ng/mL. The tested compound showed enhanced sensitivity to TRAIL-mediated cell death (Kim, 2008). Kim showed that butein in combination with TRAIL significantly induces apoptosis in TRAIL-resistant leukemia U937 cells by increased caspase-3 and caspase-8 activation (Kim, 2008). The sequence of a promoter region in TRAIL-R2 is different from that in TRAIL-R1, and the regulation of each TRAIL receptor is different from that of other receptors (Yoshida and Sakai, 2004). TRAIL-R2 mRNA expression was upregulated in the leukemia U937 cells and leukemia Jurkat cells after 12 h treatment with butein compared to those untreated cells. The expression of TRAIL-R1 was not significantly increased by butein (Kim, 2008). In solid tumor cells such as those in renal cancer, prostate cancer, lung cancer, and bladder cancer, the initiation of the apoptotic process is carried out mainly by the TRAIL-R2 receptor (Wu et al., 2007). Moon et al. have demonstrated that butein enhances TRAIL-induced apoptosis in hepatoma HepG2 and Hep3B cancer cells, HCT116 colon cancer cells, PC3 prostate cancer cells, and leukemia U937 cancer cells through upregulation of TRAIL-R2 (Moon et al., 2010). A combined treatment with butein and TRAIL increased caspase-3 activation in leukemia U937 cancer cells (Kim, 2008). A combination of butein and TRAIL leads to cleavage of caspase-3, -8, -9, Bid, and poly(ADP-ribose) polymerase (PARP) as well as the release of cytochrome c from the mitochondria into the cytosol in hepatoma HepG2 cancer cells (little or no change was observed in cells treated with a single agent). The combined treatment decreased the expression of Bcl-2, XIAP, IAP-1, and IAP- 2 in hepatoma cancer cells (Moon et al., 2010). The molecular target of chalcones is presented in Fig. 20.2.

Cardamonin can be found in cardamom spice and many other plant species, including Alpinia sp., Boesenbergia pandurate, Catimbium speciosum, Elettaria cardamomum, and Syzygium samarangense (Gonçalves et al., 2014; Ohtsuki et al., 2009; Simirgiotis et al., 2008). Cardamonin sensitizes TRAIL-resistant human gastric adenocarcinoma cells (AGS) gastric carcinoma cells to TRAIL through the induction of TRAIL-R1 and TRAIL-R2. Cardamonin upregulates TRAIL-R1, TRAIL-R2, and downregulates DcR1 in leukemia KMB-5, multiple myeloma U266, pancreatic cancer MiaPaCa, and prostate cancer DU145 and PC3. The tested compound induced CCAAT/enhancer-binding protein homologous protein (CHOP) expression, a transcriptional factor that regulates TRAIL-R2 expression (Ohtsuki et al., 2009). Cardamonin combined treatment with TRAIL increased caspase-3, -8, and -9 activity in a dose-dependent manner in DLD1/TR colon cancer cells, AGS gastric cancer cells, and HCT116 colon cancer cells (Ohtsuki et al., 2009; Yadav et al., 2012). Treatment of TRAIL-resistant colorectal adenocarcinoma cell line (DLD1/TR) colon cancer cells with cardamonin decreased mRNA and protein levels of antiapoptotic Bcl-xL protein.

A prenylated chalcone xantohumol is the main prenylated flavonoid present in hops (H. lupulus) (Botta et al., 2005; Stevens and Page, 2004), and isobavachalcone is found in medicinal plants such as Angelica keiskei, Broussonetia papyrifera, Psoralea corylifolia, and Maclura tinctoria (ElSohly et al., 2001; Yan et al., 2015). Szliszka et al. (2009) have shown that xanthohumol and isobavachalcone markedly augmented TRAIL-mediated apoptosis and cytotoxicity in LNCaP prostate cancer cells. Similar results were obtained for butein, licochalcone A, and chalkon. Szliszka et al. also demonstrated that chalcone, isobavachalcone, licochalcone A, and xanthohumol at concentrations of 25 μM significantly increased TRAIL-R2 protein levels of HeLa cervical cancer cells after 24-h (Szliszka et al., 2012). The studies were continued by Kłósek, who showed that xanthohumol sensitizes cancer cells to TRAIL-mediated apoptosis through activation of caspases-3, -8, and -9 and activation of Bid increase the expression of Bax, decrease of the expression of Bcl-xL, and decrease the mitochondrial membrane potential. No change was observed in the expression of death receptors on the surface of LNCaP cancer cells (Kłósek, 2014).

Isoliquiritigenin isolated from the roots of plants belonging to Glycyrrhiza uralensis, Glycyrrhiza glabra, and Mongolian glycyrrhiza have many biological properties (Peng et al., 2015). Yoshida et al. have shown that isoliquiritigenin increases the level of TRAIL-R2 but not TRAIL-R1 through activation of caspase-8, -10, -9, and -3 in HT29 colon cancer cells (Yoshida et al., 2008). The tested compound did not significantly increase the levels of the pro-apoptotic protein Bax and antiapoptotic proteins Bcl-2 and Bcl-xL.

Flavokawain A, B, and C constitute about 0.46%, 0.015%, and 0.012% of kava extracts (Dharmaratne et al., 2002). Flavokawain B found in Piper methysticum (Kava) has anticarcinogenic properties (Lebot et al., 2014). Tang et al. demonstrated that flavokawain B induces apoptosis in DU145 and PC3 prostate cancer cells via activation of caspases-3, -8, and -9 (Tang et al., 2010). The tested compound increases the mRNA expression of TRAIL-R2 in PC3 cancer cells and enhances TRAIL-induced apoptosis. Tang et al. have also shown that flavokawain B activates the pro-apoptotic protein Bax and mitochondrially mediated apoptotic pathway by upregulation of Bim and Puma. The tested compound also decreased expression of inhibitors of apoptosis proteins XIAP and survivin in PC3 and DU145 prostate cancer cells (Tang et al., 2010).

In summary, chalcones in combination with TRAIL increase the expression of death receptors and pro-apoptotic proteins and also decrease the expression of antiapoptotic proteins in many cancer cells. Molecular targets of chalcones in the TRAIL signaling pathway lead to sensitization of cancer cells to TRAIL-mediated apoptosis. Chalcones have potential chemopreventive effects and may be a therapeutic strategy for malignant diseases.

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