Genes Nutr (2011) 6:125–147 DOI 10.1007/s12263-011-0210-5 RESEARCH PAPER Dietary chalcones with chemopreventive and chemotherapeutic potential Barbora Orlikova • Deniz Tasdemir • Frantisek Golais • Mario Dicato • Marc Diederich Received: 23 July 2010 / Accepted: 6 January 2011 / Published online: 4 February 2011 Ó Springer-Verlag 2011 Abstract Chalcones are absorbed in the daily diet and Introduction appear to be promising cancer chemopreventive agents. Chalcones represent an important group of the polyphenolic Polyphenols represent one of the most prevalent classes of family, which includes a large number of naturally occurring compounds found in our daily diet [171]. Over the last ten molecules. This family possesses an interesting spectrum of years, increasing attention has been dedicated to chalcones biological activities, including antioxidative, antibacterial, because of their interesting biological activities. Indeed, anti-inflammatory, anticancer, cytotoxic, and immuno- chalcones constitute an important group of natural com- suppressive potential. Compounds of this family have been pounds that are especially abundant in fruits (e.g., citruses, shown to interfere with each step of carcinogenesis, apples), vegetables (e.g., tomatoes, shallots, bean sprouts, including initiation, promotion and progression. Moreover, potatoes) and various plants and spices (e.g., licorice),— numerous compounds from the family of dietary chalcones many of which have been used for centuries in traditional appear to show activity against cancer cells, suggesting that herbal medicine [29]. Chemically, chalcones are open- these molecules or their derivatives may be considered as chain flavonoids bearing two aromatic rings linked by a potential anticancer drugs. This review will focus primarily three-carbon enone moiety (Fig. 1). The majority of the on prominent members of the chalcone family with an content of chalcones in citrus fruits and various plants is 1,3-diphenyl-2-propenon core structure. Specifically, the mediated through the formation of 4,20,40,60-tetrahydroxy- inhibitory effects of these compounds on the different steps chalcone (also known as naringenin chalcone (1))by of carcinogenesis that reveal interesting chemopreventive chalcone synthase (Fig. 2)[77]. Naringenin chalcone (1) and chemotherapeutic potential will be discussed. also plays an essential role in the flavonoid biosynthetic pathway and contributes significantly to the total amount of Keywords Diet Á Chalcone derivatives Á plant flavonoids [35]. Although chalcones occur naturally, Chemoprevention Á Chemotherapy they could be available in larger amounts through an effi- cient and simple synthesis. Briefly, synthesis through base- catalyzed Claisen–Schmidt condensation of an aromatic & B. Orlikova Á M. Dicato Á M. Diederich ( ) aldehyde and an appropriate ketone in a polar solvent Laboratoire de Biologie Mole´culaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hoˆpital Kirchberg, (methanol or ethanol) renders them a readily available 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg nutrition component/supplement in either natural or syn- e-mail: [email protected] thesized form [147] (Fig. 3). The present paper is primarily concerned with chalcone D. Tasdemir Department of Pharmaceutical and Biological Chemistry, derivatives found in edible plants, fruits, and vegetables The School of Pharmacy, University of London, and with their positive effects in cancer chemoprevention 29-39 Brunswick Square, London WC1N 1AX, UK and carcinogenesis. Cancer chemoprevention can target each step of carcinogenesis with natural or synthetic sub- F. Golais Department of Microbiology and Virology, Faculty of Sciences, stances [160]. Because of unsatisfactory cancer treatment Comenius University, Bratislava, Slovakia options and adverse side effects caused by currently used 123 126 Genes Nutr (2011) 6:125–147 Polyphenols Inflammation cell-signaling pathways targeted by chalcones Phenolic acidsFlavonoids Stilbenes Lignans The tight interplay between chronic inflammation and cancer was first established and carefully documented by Virchow Chalcones Isoflavonoids in 1863 when he observed leukocytes in neoplastic tissues. Flavonols Anthocyanidins Since then, many scientists have provided evidence under- Flavones Flavanones lining the strong dependency between these two processes. 3 Natural compounds, including chalcones, have been shown 2 4 B 1 5 6 to interact with, abrogate, and abolish inflammatory signal- 3' α 4' 2' A 5' 1' β ing (see Fig. 4). Moreover, a single compound can target 6' multiple signaling events and contribute to inhibition of the O synthesis of inflammatory mediators. Fig. 1 Schematic representation of main polyphenol family mem- Nuclear factor (NF)-jB is a mediator of inflammatory bers. Polyphenols are subdivided into 4 main classes—phenolic acids, diseases and cancer and has been shown to induce resistance to flavonoids, stilbenes, and lignans—according to the number of phenol various chemotherapeutic agents. This transcription factor is rings they include and the structural elements that bind these rings together [114]. Flavonoids can be further divided into various implicated in immunity, anti-apoptosis, proliferation, and subclasses of which chalcones, flavonols, flavones, flavanones, activation of more than 550 target genes involved in tumor anthocyanidins, and isoflavonoids are the most common. The core promotion, angiogenesis, and metastasis. The canonical NF- 1,3-diphenyl-2-propenon chalcone structure is shown jB pathway is characterized by a cascade leading to activation of the functional heterodimer p50/p65. After stimulation by chemotherapeutic compounds, great emphasis has been put tumor necrosis factor (TNF)a, activation of the Ij kinase on the use of non-toxic dietary substances and botanical (IKK) complex leads to phosphorylation of the inhibitory products, either alone or in a co-treatment. subunit IjBa followed by subsequent proteasomal degrada- Various chalcones completely inhibit different steps of tion. As a result, NF-jB p50/p65 translocates to the nucleus carcinogenesis from the very early stages, including tumor and transcription is activated. initiation, through promotion, progression, angiogenesis, Besides NF-jB signaling, other pathways are strongly and invasion, to the very late stages leading to metastasis. linked to inflammation processes, including extracellular They are also strongly implicated in the negative regulation signal-regulated kinase (ERK), c-Jun N-terminal kinases of cell cycle progression and favor cell death mechanisms, (JNK), and p38 signal transduction pathways. The ERK1/ predominantly apoptosis, in transformed cells. Moderation 2-mediated signaling pathway is activated by growth fac- of these processes is generally associated with the involve- tors, cytokines, carcinogens, or viral proteins. Initially, this ment of chalcones in an elaborate network of inflammatory pathway was thought to be limited exclusively to cell cell-signaling pathways that largely contribute to tumor growth and proliferation, but there is growing evidence promotion. indicating its involvement in several inflammatory pro- This review will focus on members of the chalcone class cesses [136]. The family of JNK enzymes is implicated in with the 1,3-diphenyl-2-propenon core structure and the cell proliferation, survival, and apoptosis through the inhibitory effect of these compounds on the different steps activation of stress and inflammation. Inhibition of JNK- of carcinogenesis that highlight their interesting chemo- mediated AP-1 activation is a promising approach for preventive and chemotherapeutic potential. inhibition of the inducible expression of inflammatory CO-S-CoA OH HO OH OO + CoA HO S Chalcone synthase OH O OH 4-Coumaroyl- CoA (3x) Malonyl-CoA Naringenin chalcone Fig. 2 Biosynthesis of naringenin chalcone in plants and citruses. resulting in the formation of naringenin chalcone, which acts as a The condensation of three molecules of malonyl-CoA and one substrate for further synthesis of flavonoids molecule of 4-coumaroyl-CoA is catalyzed by chalcone synthetase 123 Genes Nutr (2011) 6:125–147 127 OH OH O HO OH HO OH O OH O OH O O 1 naringenin chalcone 2 isoliquiritigenin 3 1,2-dihydroparatocarpin A OH HO OH OH H O O OH OH O OH HO OH HO H HO O OH HO O O OH O OH O 4 isoliquiritin apioside 5 xanthohumol 6 broussochalcone A OH OH H3CO OH HO OH HO OH OH O O-Glc O OH O 7 phloretin 8 phloridzin 9 myrigalone B OH O OCH3 OH HO OH O O O 10 chalcone 11 2-hydroxychalcone 12 xanthohumol B OH OH OH HO OCH3 HO OCH3 HO OH OH O OH O OH O 13 xanthohumol D 14 dihydroxanthohumol 15 isobavachalcone CH3 OH OH CH3 OH HO HO OH OCH3 O O OH O 16 butein 17 4-hydroxychalcone 18 licochalcone A Fig. 3 Chemical structures of naturally occurring chalcone derivatives genes in cancer and other pathologies [115]. The p38 mitogen- Finally, the crosstalk of these pathways with NF-jB cell activated protein kinase (MAPK) pathway is critical for the signaling contributes to induction of key inflammatory synthesis and activity of multiple pro-inflammatory cytokines enzymes such as cyclooxygenase (COX)-2 and inducible (TNF-a, interleukin (IL)-1, IL-6, IL-8). nitric oxide synthase (iNOS) [27]. 123 128 Genes Nutr (2011) 6:125–147 OH OH OH HO HO HO OH OH OH OCH3 OCH3 OH O O OCH3 O 19 7,9,2´,4´-tetrahydroxy-8-isopentenyl-5-methoxychalcone 20 licochalcone B 21 licochalcone D HO OH H3CO OCH3 OCH3 HO O HO OCH3 OH OH HO HO OH OH O OH O O HO OH O O HO HO 22 cardamonin 23 flavokawain A 24 hydroxysafflor yellow A OH OH OH OH HO O OH OH H3CO OH O HO OH O OH HO O O OH HO OH O OH OH O 25 isobutrin 26 desmethylxanthohumol 27 asebogenin O-Glc OH HO HO OH HO OCH3 O O OH O 28 isoliquiritigenin 2´-methyl ether 29 2´,4´-dihydroxychalcone 30 isoliquiritin OH HO OCH3 H3CO OH HO OH O OH O O 31 ON-III 32 2´-hydroxy-4´-methoxychalcone 33 xanthoangelol OH OCH HO 3 H3CO OH OH OCH HO 3 OH O OH O OH O 34 4-hydroxyderricin 35 uvaretin 36 isouvaretin Fig. 3 continued It has been reported that chalcone (10) provided two abrogated time and dose dependently the activation of distinct cytoprotective mechanisms, depending on the signal transducer and activator of transcription (STAT)3 duration of pre-treatment.