JBA-06801; No of Pages 10 Biotechnology Advances xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv

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Research review paper

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Michael Schnekenburger a, Mario Dicato a, Marc Diederich b,⁎ a

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a r t i c l e

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Available online xxxx

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Keywords: Epigenetics Natural compounds Cell death Proliferation Clinical trials Cancer therapy Cancer prevention

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Introduction . . . . . . . . . . . . . . Plant-derived epigenetic modulators . . . 3,3-Diindolylmethane . . . . Butyrate and its derivatives . Curcumin . . . . . . . . . (−)-Epigallocatechin-3-gallate Genistein and daidzein . . . Nordihydroguaiaretic acid . . Quercetin . . . . . . . . . Resveratrol . . . . . . . . . Sulforaphane . . . . . . . . Critical assessment . . . . . . . . . . . Conclusions and further directions . . . . Acknowledgements . . . . . . . . . . References . . . . . . . . . . . . . .

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Introduction

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The field of epigenetics investigates heritable changes in phenotype (i.e. gene expression) without a change in the primary DNA sequence. Epigenetic mechanisms namely DNA methylation, histone modifications, and regulatory RNA-mediated gene silencing (non-coding RNA) synergize to sculpt chromatin structure and tune gene expression and

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Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery. © 2014 Published by Elsevier Inc.

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Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea

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Plant-derived epigenetic modulators for cancer treatment and prevention

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⁎ Corresponding author. Tel.: +82 2 880 8919. E-mail address: [email protected] (M. Diederich).

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therefore are essential for normal development and differentiation of cells. Consequently, epigenetic alterations are associated to the onset and development of cancer (Florean et al., 2011; Karius et al., 2012; Schnekenburger and Diederich, 2011, 2012). In human, DNA methylation corresponds to the addition of a methyl group to cytosine within CpG dinucleotides to form 5-methylcytosine. This reaction is catalyzed by the DNA methyltransferase (DNMT) family. Among this family, DNMT1 is referred as the maintenance methyltransferase, whereas the isoenzymes DNMT3A and 3B are considered as de novo methyltransferases. On a genome-wide scale, CpGs occur at low

http://dx.doi.org/10.1016/j.biotechadv.2014.03.009 0734-9750/© 2014 Published by Elsevier Inc.

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

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Plant-derived epigenetic modulators

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Multiple reports suggested that epigenetic alterations associated to the ethology of cancer are caused by unbalanced activities and overexpression of epigenetic effectors (Bannister and Kouzarides, 2011; Seidel et al., 2012a). Accordingly, the development of drugs able to inhibit epigenetic effectors and reverse epigenetic alterations, referred as epigenetic drugs, has expanded over the past years. Research in the field of epigenetic drugs leads to the identification of four molecules that gained FDA approval. Among them, two DNMTi, 5azacytidine (azacitidine; Vidaza) and 5-aza-2'-deoxycytidine (decitabine; Dacogen) were approved for the treatment of myelodysplastic syndrome almost 10 years ago and they are under clinical trials for various cancer subtypes (Seidel et al., 2012a). These two DNA demethylating agents used alone or in combinatory treatments with conventional antineoplastic drugs or with HDAC inhibitors (HDACi) were widely studied and have been shown to prevent or treat cancer through various mechanisms. These effects include, for the most common, upregulation of TSGs, growth arrest, cell cycle perturbation, inhibition of DNA repair, angiogenesis, migration, invasion and metastasis, restoration of differentiation mechanisms, and induction of cell death (Charlet et al., 2012; Ghoshal and Bai, 2007; Schnekenburger et al., 2011; Seidel et al., 2012a). Nowadays, an extensive list of HDACi with miscellaneous structures has been discovered. They display broad spectrum and potent antitumor activities including hyperacetylation of histone and non-histone proteins associated to cell cycle arrest, inhibition of differentiation, telomerase activity and angiogenesis, modulation of metabolism activity, and induction of cell death (Folmer et al., 2010; Seidel et al., 2012a, 2012b). Two HDACi, suberoyanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®) and FK228 (Romidepsin, Istodax®), received FDA approval for the treatment of cutaneous T-cell lymphoma (CTCL). Moreover, multiple completed clinical trials and numerous other ongoing trials using an HDACi as a single agent or in combination for anti-cancer therapy (http://www.clinicaltrial.gov/). Besides these four drugs, many molecules reported to target and modulate epigenetic mechanisms that are plant-derived compounds showing promising potential for cancer prevention and therapy by modulating most hallmarks of cancer (see Table 1). We will focus on plant-derived compounds that are the more advanced in clinical set up (the structures of these molecules are presented in Fig. 1) and for which there is more evidence of a link between their anti-cancer properties and epigenetic effects targeting histone modifications and DNA methylation.

103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 Q3 123 124 125 126 127 128 129

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97 98

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91 92

Butyrate and its derivatives

141

133 134 135 136 137 138 139 140

Sodium butyrate is a short-chain fatty acid generated during gut flora-mediated fermentation of dietary fibers, where it serves as energy to colonic cells. In the 70s, butyrate was initially described to promote cell differentiation (Leder and Leder, 1975) and then reported to inhibit HDAC activity and to cause rapid histone hyperacetylation in leukemia cells (Sealy and Chalkley, 1978). Subsequently, multiple studies have reported that butyrate has pleiotropic anti-cancer effects in various models including cell cycle arrest, inhibition of proliferation, inflammation and oxidative stress, modulation of detoxification potential, and induction of differentiation and apoptotic cell death (Davie, 2003; Myzak and Dashwood, 2006; Scharlau et al., 2009; Schnekenburger et al., 2006). Based on these observations, the potential of butyrate was highly considered to prevent inflammation-mediated ulcerative colitis and colorectal cancer by a continuous exposure to dietary fiber along human being life. Besides its HDACi inhibitory activity, butyrate was more recently highlighted to induce DNA demethylation most likely related to changes in chromatin structure (Spurling et al., 2008). Remarkably, several butyrate derivatives acting as HDACi are also undergoing clinical trials such as sodium phenylbutyrate and pivaloyloxymethyl butyrate (Pivanex, AN-9).

142 143

Curcumin

162

Curcumin (diferuloylmethane) is a naturally occurring flavonoid derived from the rhizome of Curcuma longa. Curcumin is one of the most widely studied and characterized phytochemical for its anti-cancer and chemopreventive properties. Indeed, this well tolerated spice compound possesses anti-oxidant, anti-inflammatory, anti-angiogenic, antiproliferative and pro-apoptotic activities against several types of cancer (Ahmad et al., 2012; Duvoix et al., 2003a, 2003b, 2005; Gupta et al., 2010). Evidence accumulates that these anti-cancer properties might result from epigenetic changes triggered by curcumin and leading to a modulation of the expression of genes controlling these pathways. The effect of curcumin on epigenetic mechanisms was recently deeply reviewed by Teiten et al. (Teiten et al., 2013). Curcumin was reported to decrease both global DNA methylation and local promoter methylation. Furthermore, depending on cellular models, curcumin decreases HAT activities and histone acetylation or reduces the expression of several HDAC isoenzymes accompanied by increased histone acetylation. Recently, curcumin was reported to decrease expression of the HMT EZH2 and the level of the repressive histone mark H3K27me3 (Balasubramanyam et al., 2004; Chen et al., 2007; Hua et al., 2010; Kang et al., 2005; Khor et al., 2011; Liu et al., 2005, 2009b; Marcu et al., 2006; Shu et al., 2011).

163 164

(−)-Epigallocatechin-3-gallate

184 Q4

(−)-Epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol of green tea, has been extensively reported for its in vitro and in vivo anti-cancer activities including anti-oxidant, antiinflammatory anti-proliferative, anti-invasive, anti-angiogenic and

185

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88

131 132

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74 75

3,3-Diindolylmethane is a digestive product of indole-3-carbinol found in cruciferous vegetables. Indole-3-carbinol is a well-recognized chemopreventive agent displaying many biological activities such as inhibition of inflammation and angiogenesis, decrease of proliferation and promotion of tumor cell death that may account for its anti-cancer properties (Acharya et al., 2010; Rogan, 2006). Data suggest that these effects might be due, at least partially, of the inhibitory effect of 3,3diindolylmethane on HDAC activity by inducing proteasome-mediated downregulation of several HDAC isoenzymes (HDAC1-3, 8) (Beaver et al., 2012; Li et al., 2010).

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130

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3,3-Diindolylmethane

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69 70

frequency and are usually methylated. However, there are specific DNA regions of the genome where CpGs are concentrated at a much higher frequency, called CpG islands, mainly detected in or near gene promoter regions. Under normal conditions, these regions are largely unmethylated for most genes, whereas in cancer cells, CpG islands in tumor suppressor genes (TSGs) are frequently hypermethylated and associated to transcriptional gene silencing and inactivation of TSG functions (Esteller, 2007; Jones, 2012; Kulis and Esteller, 2010). Acetylation and methylation of lysine-rich histone tails are two major post-translational modifications involved in the regulation of chromatin structure and gene expression. Acetylation is regulated by the balanced enzymatic activities of members of histone acetyltransferase (HAT) and histone deacetylase (HDAC) families. Similarly, methylation is controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs). Alteration of histone modification profiles causing TSG silencing is associated to carcinogenesis (Bannister and Kouzarides, 2011; Seidel et al., 2012a). Noteworthy, the role of these enzymes in the modulation of covalent post-translational modifications of non-histone proteins is now emerging as a key mechanism in regulating protein functions in normal cell biology and cancer pathogenesis (Batta et al., 2007; Zhang et al., 2012).

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Genistein and daidzein are abundant polyphenols found in soybean. These two phytochemicals were widely studied and reported to inhibit oxidative stress, angiogenesis, modulation of cell cycle regulation, and induction of apoptosis (Rietjens et al., 2013). Epidemiological studies suggest that soy product consumption has chemopreventive virtues against cancer (Rietjens et al., 2013). Accordingly, genistein and daidzein are under clinical trials for chemotherapeutic and chemopreventive purposes in several cancer subtypes. Interestingly both compounds were reported to inhibit DNMT1 activity, decrease methylation of promoter methylation of TSGs leading to their reactivation in cancer cells. Furthermore, genistein induce histone acetylation by inhibiting HDACs and activating HATs (Bosviel et al., 2012a; Fang et al., 2005a, 2005b; Kikuno et al., 2008; Majid et al., 2008, 2009, 2010).

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Nordihydroguaiaretic acid

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238 239

Nordihydroguaiaretic acid (NDGA, Masoprocol) is a phenolic lignan acting as a potent anti-oxidant agent and lipoxygenase inhibitor with well-recognized beneficial health effects (Lu et al., 2010). NDGA displays a broad spectrum of biological activities; it reduces cancer cell proliferation in vitro and in vivo and has cancer chemopreventive activity in both chemically- and UV-induced models of carcinogenesis. The mechanisms responsible for these effects are still under investigation but it has been demonstrated that NDGA inhibits DNMT1 activity leading to global DNA demethylation as well as gene promoter demethylation and reactivation (Cui et al., 2008a, 2008b; Li et al., 2004).

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Quercetin

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Quercetin is a polyphenol largely present in the plant kingdom and has been shown to strongly inhibit oxidative stress and inflammation. Quercetin displays a broad spectrum of anti-cancer activities and accumulating evidence suggests also cancer preventive properties (Murakami et al., 2008). Interestingly, quercetin was reported to enhance the activity of the NAD+-dependent HDAC sirtuin (SIRT) 1 in yeast and to decrease DNMT activity leading to p16 promoter demethylation and gene reactivation (Howitz et al., 2003; Tan et al., 2009). It remains to determine

196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213

251

Resveratrol is a popular polyphenol found in grape and grape products such as red wine. By modulating various pathways important for cancer development, this stilbene has been shown to display anticancer properties mediated by anti-oxidant and anti-inflammatory activities, inhibition of cell proliferation, induction of anti-angiogenic response, and increased rate of apoptosis (Aluyen et al., 2012). Robust preclinical and clinical studies suggest that resveratrol possesses health-promoting benefits, especially in the field of prevention of various pathologies including cancer (Scott et al., 2012). The mechanisms responsible for such effects are still under evaluation. The most debated question is related to resveratrol-mediated SIRT1 activation that was initially demonstrated to increase lifespan in yeast and Caenorhabditis elegans (Howitz et al., 2003); later this observation was though to be an artifact from in vitro fluorimetric-based assays (Pacholec et al., 2010). Nonetheless, multiple studies have demonstrated that resveratrol acts as a SIRTi, a caloric restriction mimetic and that cancer preventive effects of resveratrol are dependent on SIRT activity (Farghali et al., 2013). For instance, resveratrol poorly protects SIRT1-null mice bearing the Apc(min) mutation of developing tumors (Boily et al., 2009). Besides its effect of SIRT, resveratrol was reported to be a weak DNMTi, which reduces DNMT1 expression and methylation of RARβ and PTEN genes (Paluszczak et al., 2010; Stefanska et al., 2010; Stefanska et al., 2012).

252 253

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Resveratrol

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Genistein and daidzein

193 194

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191 192

whether these molecular targets are relevant to the cancer preventive 249 properties of quercetin. 250

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pro-apoptotic effects (Shirakami et al., 2012). Furthermore, based on various animal models of induced carcinogenesis, EGCG displays cancer preventive activities (Shirakami et al., 2012). However, the chemopreventive properties of EGCG are discussed controversially since animal data supported by some epidemiological studies suggesting that green tea may decrease cancer risk but others failed to support these findings (Khan and Mukhtar, 2010). Therefore, health promoting and cancer preventing effects of EGCG are still under intensive investigations including clinical studies to fully unravel its mechanism of actions and it should determine whether EGCG could be utilized as a chemotherapeutic agent or would be more beneficial as a dietary supplement. Nonetheless, over the past decade, several reports highlighted the effects EGCG on the epigenetic machinery that might account for its anti-cancer activities. EGCG was reported to act as a DNA demethylating agent by inhibiting DNMT1 and to decrease promoter methylation of various TSGs leading to gene reactivation (Fang et al., 2003; Lee et al., 2005b). For instance, it was demonstrated that the prototypical hypermethylated biomarker glutathione S-transferase pi (GSTP1) gene frequently methylated in cancer (Duvoix et al., 2003c; Karius et al., 2011) was reactivated after DNA demethylation after exposure to green tea polyphenols in prostate cancer cells (Pandey et al., 2010). In epidermal tumor models, EGCG reduces also HAT activity and the acetylation levels of histones and non-histone proteins such as NF-κB (Choi et al., 2009a). More recently, EGCG was reported to decrease the expression of the HMT EZH2 accompanied by reduced H3K27me3 levels (Balasubramanian et al., 2010).

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Sulforaphane

254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274

Sulforaphane is a dietary isothiocyanate found in cruciferous vegetables. Sulforaphane interferes with multiple pathways leading to decreased proliferation and induction of apoptosis. Furthermore, multiple reports pointed out its preventive properties against cancer development as this phytochemical is able to induce enzymes involved in cell detoxification and to prevent carcinogenesis induced in animal models (Amin et al., 2009; Ho et al., 2009). Accumulating evidence suggest that the anti-cancer properties of sulforaphane could be at least partially mediated by its effect on epigenetic mechanisms. Indeed, sulforaphane is a well-described HDACi increasing total and promoter-specific histone acetylation in cancer cells and in human subjects (Myzak et al., 2004; Myzak et al., 2007). In silico and in vitro experiments suggest that the HDAC inhibitory activity of sulforaphane is owned by its metabolite sulforaphane–cysteine (Ho et al., 2009; Myzak et al., 2004). More recently, the effect of sulforaphane as a demethylating agent was reported, sulforaphane was found to down-regulate the expression of DNMT1 and 3B leading to cyclin D2 promoter demethylation and gene expression (Hsu et al., 2011).

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Critical assessment

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During decades, the best way to fight against cancer was to destroy pathologically altered cells with cytotoxic anti-neoplastic drugs, which is still the standardized regimen for chemotherapy. However, it is now considered that chemoprevention, the use of natural dietary agents and/or synthetic compounds in healthy individuals without signs of malignancy, may represent a better chance to avoid the burden of cancer by delaying, preventing, or even reversing the development of tumor cells (Schnekenburger and Diederich, 2012). Interestingly, many epidemiological studies and research data suggest that a diet rich in fruit and vegetables, a relatively easy to goal to achieve, has many beneficial health effects and may reduce cancer incidence by promoting a combination of effects including antiinflammatory, anti-oxidant, pro-apoptotic, pro-differentiating, antiangiogenic and anti-invasive activities. These effects are considered to be mediated by phytochemicals with multiple biological activities

294 295

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292

296 297 298 299 300 301 302 303 304 305 306 307 308

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Table 1 Plant-derived epigenetic modulators with anti-cancer properties. Names in bold correspond to compounds under clinical trials for cancer prevention or therapy (http://www.clinicaltrial.gov/).

t1:4

Chemical class

Compound

Plant source

Epigenetic target (s) and mechanism (s)

References

t1:5

Alkaloid

Mahanine

Murraya koenigi, Micromelum minutum

Inhibits DNMT activity, decreases DNMT expression and induces gene reactivation (RASSF1A) DNMT1i, induces DNA demethylation

Agarwal et al. (2013) and Jagadeesh et al. (2007)

t1:6

Procainamide

t1:7

Sanguinarine

t1:8

U

Anthocyanidin

N

t1:10

Anthraquinone

Emodin

Pigment found in apple, plum, red cabbage, red onion and most red berries: grape, cherry, strawberry, blueberry… Common plant pigment found in grape, cranberries, blueberries, pomegranate and in flowers such as violas and delphiniums Rheum emodi (rhubarb), Fallopia japonica, buckthorns

t1:11 t1:12

Betacyanin Catechin

Betanin Catechin/epicatechin EGCG

Beta vulgaris (beetroot) Camellia sinensis (green tea) Camellia sinensis (green tea)

Epicatechin gallate Epigallocatechin Theaflavin 3,3′-digallate Selenium Butein Homobutein Isoliquiritigenin Marein Phloretin (dihydrochalcone) Dihydrocoumarin Hesperetin Naringenin Apigenin

Camellia sinensis (green tea) Camellia sinensis (green tea) Camellia sinensis (Black tea) nuts, cereals, mushrooms Toxicodendron vernicifluum Trifolium subterraneum, Erythrina abyssinica Glycyrrhiza glabra (liquorice) Coreopsis maritima Apples Melilotus officinalis (sweet clover) Citrus fruits Grapefruit Apium graveolens (celery), Petroselinum crispum (parsley)

t1:27 t1:28

Baicalein Flavone

Scutellaria baicalensis, Oroxylum indicum Feijoa sellowiana (pineapple guava)

t1:29

Luteolin

Terminalia chebula, many culinary herbs (thyme, rosemary…), carrots Vitis amurensis Pigment found in many fruits including strawberry and mango

t1:9

Cyanidin

Synthetic derivative of cocaine isolated from Erythroxylum coca plants Sanguinaria canadensis, Argemone mexicana, Papaver somniferum (Opium poppy)

Delphinidin

t1:13

t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26

t1:30

Chalcogen Chalcone

Coumarin Flavanone Flavone

Flavonol

Amurensin G Fisetin

t1:31 t1:32

Galangin

t1:33

Kaempferol Myricetin

t1:34 t1:35 t1:36

Quercetin Indole

3,3-Diindolylmethane

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R

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Alpinia officinarum, Alpinia galanga, Helichrysum aureonitens, Propolis Found in common fruits and vegetables (tea, tomato, cruciferous vegetables, apple…) Found in walnuts and many other sources among fruits, herbs, vegetables Frequently found in fruits and vegetables

Selvi et al. (2009)

HMTi (G9a), decreases histone methylation (H3K4 and H3R17); in vitro HATi, decreases histone acetylation In vitro DNMTi

C

C

Lee et al. (2005a)

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Paluszczak et al. (2010)

HATi (p300, CBP), decreases protein acetylation (NF-κB p65)

Seong et al. (2011)

Emodin decreases pH3Ser10 and increases H3K27me3 contributing to gene silencing in bladder cancer cells In vitro DNMTi In vitro DNMTi HATi (p300), decreases histone acetylation; DNMTi, decreases DNMT expression and induces DNA methylation and gene reactivation (p16, RARbeta, MLH1 and MGMT) In vitro DNMTi In vitro DNMTi In vitro DNMTi DNMTi, decreases DNA methylation In vitro HDACi In vitro HDACi In vitro HDACi In vitro HDACi In vitro DNMTi SIRTi (SIRT1 and 2), increases p53 acetylation In vitro DNMTi In vitro DNMTi In vitro DNMTi; decreases HDAC activity through a downregulation of HDAC1 and 3 expression and increases histone acetylation In vitro DNMTi HDACi, increases histone and non-histone acetylation levels In vitro DNMTi

Cha et al. (2013)

Paluszczak et al. (2010) Fang et al. (2003) and Lee et al. (2005b) Choi et al. (2009a), Fang et al. (2003) and Lee et al. (2005b)

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Fang et al. (2003) and Lee et al. (2005b) Fang et al. (2003) and Lee et al. (2005b) Rajavelu et al. (2011) Davis et al. (2000) and Fiala et al. (1998) Orlikova et al. (2012) Orlikova et al. (2012) Orlikova et al. (2012) Orlikova et al. (2012) Paluszczak et al. (2010) Olaharski et al. (2005) Fang et al. (2007) Fang et al. (2007) Fang et al. (2007) and Pandey et al. (2012)

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R O

O

Paluszczak et al. (2010) Bontempo et al. (2007)

In vitro SIRTi In vitro DNMTi; activates SIRT from Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster In vitro DNMTi

Fang et al. (2007)

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Oh et al. (2010) Howitz et al. (2003), Lee et al. (2005b) and Wood et al. (2004)

Paluszczak et al. (2010)

Decreases HDAC activity and increases acetylation

Berger et al. (2013)

In vitro DNMTi

Fang et al. (2007), Lee et al. (2005b) and Paluszczak et al. (2010) Howitz et al. (2003) and Tan et al. (2009)

In vitro SIRTa; DNMTi, induces p16 promoter demethylation and gene expression

Beaver et al. (2012) and Li et al. (2010)

M. Schnekenburger et al. / Biotechnology Advances xxx (2014) xxx–xxx

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

t1:1 t1:2 t1:3

t1:37

Isoflavandiol

Equol

Gut product of daidzein

t1:38

Isoflavone

Biochanin A

Glycine max (soy), Trifolium pratense (red clover), Cicer arietinum (chickpea), Arachis hypogaea (peanut) Pueraria mirifica, Pueraria lobata, Glycine max (soy)

t1:39

Daidzein Genistein

U

t1:40 t1:41 t1:42 t1:43

Isothiocyanate

t1:44

N

Osajin Pomiferin Phenethyl isothiocyanate

Glycine max (soy)

C

Maclura pomifera (osage orange) Maclura pomifera (Osage orange) Cruciferous vegetables

O

R

Phenylhexyl isothiocyanate

Derivative of natural isothiocyanates

Sulforaphane

Cruciferous vegetables

Nordihydroguaiaretic acid

Larrea tridentata (creosote bush)

Silibinin Allyl mercaptan Diallyl disulfide S-allylmercapto-L-cysteine

Silybum marianum (milk thistle) Allium sp. (onion, garlic, shallots) Allium sp. (onion, garlic, shallots) Allium sp. (Onion, Garlic, shallots)

Anacardic acid

Anacardium occidentale (cashew nut)

t1:52

Caffeic acid

t1:53

Chlorogenic acid

t1:54

Gallic acid

t1:55

Hydroxycinnamic acid

t1:56 t1:57 t1:58 t1:59

Protocatechuic acid Rosmarinic acid Sinapic acid Syringic acid Curcumin

Coffea arabica or canephora (coffee), artichoke, pear, basil, thyme, oregano, apple Coffea arabica or canephora (coffee), strawberries, pineapple, sunflower, blueberries Common in fruits (mango, blackberry…) and a number of plants (tea, areca nuts) Not clear what hydroxycinnamic acid was used in the study Green tea, olives Rosmarinus officinalis (Rosemary) Sinapis sp. (mustard) Ardisia elliptica, Tamarix aucheriana Curcuma longa (curcuma)

t1:45

Lignan

t1:46 t1:47 t1:48 t1:49 t1:50

Organosulfur

t1:51

Phenolic acid

R

E

C

t1:60

t1:61 t1:62 t1:63 t1:64 t1:65 t1:66 t1:67 t1:68

Polyisoprenylated benzophenone

Polyphenol

Polyvanillic acid

Clusianone Garcinol Guttiferone A Guttiferone E Nemorosone Brazilin

Garcinia sp., Rheedia sp., Symphonia sp. Garcinia indica Garcinia sp., Rheedia sp., Symphonia sp. Garcinia sp., Rheedia sp., Symphonia sp. Clusia sp. Caesalpinia sappan

Ellagic acid

Found in numerous fruits and vegetables

T

Induces proteasome-mediated degradation of class I HDACs (HDAC1-3, 8) without affecting class II HDAC isoenzymes Induces DNA demethylation at BRCA1 and BRCA2 promoters and gene expression DNMTi, induces DNA demethylation and gene reactivation (p16, RARbeta, and MGMT) DNMTi, induces DNA demethylation and gene reactivation (p16, RARbeta, and MGMT) Reduces DNMT activity and expression, induces DNA demethylation and gene reactivation (p16, RARbeta, and MGMT); decreases HDAC activities, HATi, increases acetylation at TSG In vitro HDACi In vitro HDACi HDACi, increases histone acetylation; induces GSTP1 promoter demethylation and gene expression HDACi, increases histone acetylation; decreases p16 promoter methylation HDACi, increases histone acetylation; decreases DNMT expression, induces DNA methylation and gene reactivation (cyclin D2) Decreases DNMT1 activity, induces DNA methylation and gene reactivation (p16, E-caderhin) DNMTi, increases histone acetylation HDACi, increases histone acetylation HDACi, increases histone acetylation Inhibits HDAC and HAT activities; increases H2A, H2B, H3 and H4 acetylation HATi (PCAF, p300), decreases basal and induced protein acetylation In vitro DNMTi, decreases RARbeta promoter methylation In vitro DNMTi, decreases RARbeta promoter methylation In vitro HATi (p300, CBP, PCAF, Tip60), decreases protein acetylation (NF-κB p65) In vitro DNMTi

Bosviel et al. (2012b) Fang et al. (2005a) Bosviel et al. (2012a) and Fang et al. (2005a) Bosviel et al. (2012a), Fang et al. (2005a), Fang et al. (2005b), Kikuno et al. (2008), Majid et al. (2008) and Majid et al. (2010) Son et al. (2007) Son et al. (2007) Wang et al. (2007) and Wang et al. (2008) Lu et al. (2008) Ho et al. (2009), Hsu et al. (2011) and Myzak et al. (2004) Cui et al. (2008a), Cui et al. (2008b) and Li et al. (2004) Cui et al. (2009) and Kauntz et al. (2013) Nian et al. (2008) Druesne et al. (2004) Lea et al. (2002)

E

Balasubramanyam et al. (2003)

D

Lee and Zhu (2006) Lee and Zhu (2006)

P

Choi et al. (2009b)

R O

In vitro DNMTi In vitro DNMTi In vitro DNMTi; HDACi, increases histone acetylation In vitro DNMTi HATi (p300), decreases histone and protein acetylation; reduces expression of several HDACs and increases histone acetylation; in vitro DNMTi, decreases DNMT1 expression, sequence-specific demethylation at promoter regions of epigenetically silenced genes; decreases HMT (EZH2) expression and H3K27me3 repressive mark In vitro HATi In vitro HATi In vitro HATi In vitro HATi HATa, increase histone acetylation Downregulation of HDAC1 and HDAC2 expression, increases histone acetylation In vitro DNMTi HDACi, increases histone and α-tubulin acetylation

O

Fang et al. (2007) Paluszczak et al. (2010) Paluszczak et al. (2010) Paluszczak et al. (2010) Paluszczak et al. (2010) Balasubramanyam et al. (2004), Chen et al. (2007), Hua et al. (2010), Kang et al. (2005), Khor et al. (2011), Liu et al. (2005), Liu et al. (2009b), Marcu et al. (2006) and Shu et al. (2011)

M. Schnekenburger et al. / Biotechnology Advances xxx (2014) xxx–xxx

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

Digestive product of indole-3-carbinol found in cruciferous vegetables

F

Dal Piaz et al. (2010) Padhye et al. (2009) Dal Piaz et al. (2010) Dal Piaz et al. (2010) Dal Piaz et al. (2010) Kim et al. (2012) Paluszczak et al. (2010) Seidel et al. (2013) 5

(continued on next page)

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Table 1 (continued)

C

Chemical class

Compound

t1:69

Protein

4-hydroxybenzoic-based compounds MCP30

Derivatives of burkinabin from Zanthoxylum zanthoxyloides (Fagara zanthoxyloides) Momordica charantia (bitter melon)

t1:70

Quinole Quinone

MC1626 Plumbagin

Sesquiterpenoid

6-methoxy-2E,9Ehumuladien-8-one Butyrate

Synthetic derivative of anacardic acid Plumbago rosea (Scarlett Leadwort) and several carnivorous plants Zingiber aromaticum (ginger)

t1:71 t1:72

Short-chain fatty acid

t1:73 t1:74

VPA

t1:75

Stilbene

Piceatannol Resveratrol

t1:76 t1:77

Terpenoid

Lycopene

t1:78 t1:79

Parthenolide PL3 (16-hydroxycleroda3,13-dien-15,16-olide) Thymoquinone Triptolide

t1:80 t1:81 t1:82 t1:83 t1:84 t1:85 t1:86 t1:87

Xanthine

Ursolic acid Theophylline

Plant source

O

R

R

E

From gut fermentation of dietary fibers

C

Derivative of valeric acid found in Valeriana officinalis (valerian) Picea abies (Norway spruces), Grape Fallopia japonica (Japanese knotweed), grape, nuts

T

Solanum lycopersicum (tomato), other red fruits and vegetables Tanacetum parthenium Polyalthia longifolia Nigella sativa Tripterygium wilfordii Mirabilis jalapa, Ocimum basilicum (Basil) Cocoa beans, tea

Epigenetic target (s) and mechanism (s)

References

Decreases HDAC1 expression and activity, increases histone acetylation HATi, reduces histone H3 acetylation HATi, decreases histone acetylation, H3K4Me3, H3S10P HDACi

Xiong et al. (2009)

HDACi, increases histone acetylation, induces RARbeta gene demethylation and expression HDACi, decreases HDAC2 expression, increases histone acetylation In vitro DNMTi; in vitro SIRTa In vitro DNMTi, downregulation of DNMT1, induces DNA demethylation and gene reactivation (RARbeta, PTEN); SIRTa, HATi, decreases protein acetylation Induces DNA demethylation and gene reactivation (GSTP1, RARbeta, HIN-1) Decreases DNMT1 expression and DNA methylation Reduces the expression of HMT (EZH2) and H3K27 methylation HDACi, increases histone acetylation Decreases HMT (SUV39H1, EZH2) expression and histone methylation HDACi, increases histone acetylation HDACa

Davie (2003), Sealy and Chalkley (1978) and Spurling et al. (2008) Gottlicher et al. (2001) and Kramer et al. (2003)

Ruotolo et al. (2010) Dalvoy Vasudevarao et al. (2012) and Ravindra et al. (2009) Chung et al. (2008)

E

Howitz et al. (2003) and Paluszczak et al. (2010) Howitz et al. (2003), Paluszczak et al. (2010), Stefanska et al. (2010), Stefanska et al. (2012) and Yeung et al. (2004) King-Batoon et al. (2008)

D

P

Gopal et al. (2007) and Liu et al. (2009a) Lin et al. (2011)

R O

Chehl et al. (2009) Zhao et al. (2010) Chen et al. (2009) Cosio et al. (2004)

a and i after the name of targets stand for activator and inhibitor, respectively. CBP: cAMP responsive element binding protein-binding protein, DNMT: DNA methyltransferase, GSTP: glutathione S-transferase, HAT: histone acetyltransferase, HDAC: histone deacetylase, HIN: high in normal, HMT: histone methyltransferase, MGMT: O-6-methylguanine-DNA methyltransferase, MLH: mutL homolog NF-κB: nuclear factor-kappaB, PCAF: p300/CBP-associated factor, PTEN: phosphatase and tensin homolog, RAR: retinoic acid receptor, RASSF: Ras Association domain family, SIRT: sirtuin.

O

F

M. Schnekenburger et al. / Biotechnology Advances xxx (2014) xxx–xxx

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

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309 310 311 312 313 314 315 316 317 318 319 320 321

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Fig. 1. Chemical structures of selected plant-derived epigenetic modulators in clinical trials for anti-cancer therapy.

conferring the ability to counteract cell signaling cascades and mechanisms leading to genotoxic damage, redox imbalances and other forms of stresses associated or leading to a deregulation of cellular homeostasis. Accordingly, such molecules are recognized to exert pleiotropic effects, which are most likely related to the complexity of their chemical structure. Hence, the phytochemicals discussed previously have numerous intracellular targets, disturbing multiple transcription factors (e.g. activator protein-1 (AP-1) and nuclear factor kappa-light chainenhancer of activated B cells (NF-κB)) and cell signaling pathways (mitogen-activated protein kinases (MAPKs) and β-catenin) closely connected to cellular processes including proliferation, differentiation, cell death, inflammation, angiogenesis and invasion but also into the mechanisms of inflammation and carcinogenesis (Gerhauser, 2013; Huang

et al., 2011; Vanden Berghe, 2012). These pleiotropic effects might represent one of the reasons why they are efficient at killing tumor cells presenting multiple alterations of their regulatory mechanisms but with limited toxicity on normal cells. In this context, many phytochemicals where considered for chemotherapeutic purposes; however, despite a large body of evidence demonstrating promising anti-cancer properties by inhibiting cell growth and promoting apoptosis in numerous cancer models, only few natural compounds entered clinical trials as chemotherapeutic agents (Table 1). Epigenetic aberrations are potentially reversible and occur at the earliest steps of carcinogenesis, they therefore represent opportunities not only for therapeutic but also for preventive interventions (Florean et al., 2011; Schnekenburger and Diederich, 2012; Seidel et al., 2012a).

Please cite this article as: Schnekenburger M, et al, Plant-derived epigenetic modulators for cancer treatment and prevention, Biotechnol Adv (2014), http://dx.doi.org/10.1016/j.biotechadv.2014.03.009

322 323 324 325 326 327 328 329 330 331 332 333 334

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365 366 Q5

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MS is supported by a “Waxweiler grant for cancer prevention research” from the Action Lions “Vaincre le Cancer”. This work was supported by the “Recherche Cancer et Sang” foundation, the “Recherches Scientifiques Luxembourg” association, by the “Een Häerz fir kriibskrank Kanner” association, by the Action LIONS “Vaincre le Cancer” association and by Télévie Luxembourg. MD is supported by the National Research Foundation of Korea (NRF) grant for the Global Core Research Center (GCRC) funded by the Korea government, Ministry of Science, ICT & Future Planning (MSIP) (No. 2011-0030001).

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Over the past 10 years, many plant-derived compounds were identified for their anti-cancer properties with an emerging field regarding the modulation of epigenetic events. Most compounds were evaluated regarding histone modifications (mainly acetylation) and DNA methylation; however, evaluating the impact of these compounds on miRNA (Huang et al., 2011; Karius et al., 2012; Link et al., 2010; Schneider-Stock et al., 2012) and potentially other epigenetic targets is necessary to clarify the role of epigenetics on gene regulation for chemopreventive purposes and clinical applications. Another aspect is related to an improved characterization of micronutrients found in plant-based diet such as selenium and folate (Supic et al., 2013), which are also reported to influence epigenetic marks. We also need to consider the long-term and eventually trans-generational effects of sustained preventive interventions. Furthermore, there is the necessity to identify biomarkers to monitor the efficiency of preventive interventions by epigenetic modulators and eventually to predict the need of such interventions, which is going towards a personalized medical approach.

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Furthermore, as discussed in this review, a growing body of evidence is demonstrating that edible phytochemicals interfere with various epigenetic modifiers or modulate epigenetic mechanisms (Gerhauser, 2013; Huang et al., 2011; Schneider-Stock et al., 2012; Vanden Berghe, 2012). In this context, taking into account the pleiotropic role of epigenetic mechanisms in the regulation of gene expression and protein functions controlling all cellular processes in healthy and neoplastic cells, it is probably not presumptuous to suggest that the chemopreventive properties of these compounds are mediated at least in part by their capacity to modulate epigenetic mechanisms.

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