Cancer Letters 351 (2014) 182–197

Contents lists available at ScienceDirect

Cancer Letters journal homepage: www.elsevier.com/locate/canlet

Mini-review

Epigenetic modulators from ‘‘The Big Blue’’: A treasure to fight against cancer Michael Schnekenburger a, Mario Dicato a, Marc Diederich b,⇑ a b

Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea

a r t i c l e

i n f o

Article history: Received 19 March 2014 Received in revised form 1 June 2014 Accepted 4 June 2014

Keywords: Natural marine compounds Epigenetic DNA methylation Histone modifications Micro-RNAs Anti-cancer drugs

a b s t r a c t Cancer remains a major public health problem in our society. The development of potent novel anticancer drugs selective for tumor cells is therefore still required. Deregulation of the epigenetic machinery including DNA methylation, histone modifications and non-coding RNAs is a hallmark of cancer, which provides potential new therapeutic targets. Natural products or their derivatives represent a major class of anti-cancer drugs in the arsenal available to the clinician. However, regarding epigenetically active anti-cancer agents for clinics, the oceans represent a largely untapped resource. This review focuses on marine natural compounds with epigenetic activities and their synthetic derivatives displaying anticancer properties including largazole, psammaplins, trichostatins and azumamides. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Introduction Despite considerable progress in research and medicine, the burden of cancer in our society remains a major public health problem. Indeed, neoplastic diseases are a leading cause of death with an increasing incidence and mortality worldwide with lung, stomach, liver, colon and breast cancer causing the most cancer deaths each year. Accordingly, cancer-related deaths are predicted to continuously increase, with an estimated 13.1 million deaths

worldwide in 2030 (source World Health Organization: http:// www.who.int/mediacentre/factsheets/fs297/en/). In this context, the identification of novel chemical entities allowing the development of potential novel anti-cancer agents selective for tumor cells remains of major significance to extend the therapeutic armamentarium for successful anti-cancer therapy. The therapeutic arsenal routinely use by oncologists rely on drug discovery of chemotherapeutic drugs from natural sources either unmodified or synthetically modified forms, which for most of

Abbreviations: 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; AID, activation-induced deaminase; AML, acute myeloid leukemia; APOBEC, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; BAK, BCL2-antagonist/killer 1; BCL-2, B-cell lymphoma 2; BER, base excision repair; CBP, CREB-binding protein; CDK, cyclin-dependent kinase; CLDN4, claudin 4; CREB, cAMP response element-binding protein; DNMT, DNA methyltransferase; DNMTi, DNMT inhibitor; EGCG, epigallocatechin gallate; EHMT1, euchromatic histone-lysine N-methyltransferase 1; FAD, flavin adenine dinucleotide; FDA, food and drug administration; FOXO, forkhead box O; GCN5, general control nonderepressible 5; GNAT, GCN5-related N-acetyltransferase; GSTP, glutathione S-transferase pi; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACi, HDAC inhibitor; HDM, histone demethylase; HMT, histone methyltransferase; HOTTIP, HOXA transcript at the distal tip; HPLC, high-performance liquid chromatography; IGF2, insulin-like growth factor 2; jmj, jumonji; L3MBTL, lethal 3 MBT-like protein; LINE, long interspersed element; lincRNA, long intergenic non-coding RNA; lncRNA, long non-coding RNA; MAEL, mouse maelstrom; MBD, methyl CpG binding protein; MBT, malignant brain tumor; MCL-1, myeloid cell leukemia sequence 1; micro-RNA, miRNA; MLH1, mutL homolog 1; MLL, mixed lineage leukemia; MOZ, monocytic leukemia zinc finger protein; MYST, MOZ, Ybf2/Sas3, Sas2, Tip60; NAD, nicotinamide adenine dinucleotide; ncRNA, non-coding RNA; NF-jB, nuclear factor-kappa B; NMR, nuclear magnetic resonance; PCAF, p300/CBP-associated factor; PGC1a, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PHD, plant homeodomain; PI3K, phosphatidylinositol 3 kinase; PRMT, protein arginine Nmethyltransferase; PsA, psammaplin A; PTEN, phosphatase and tensin homolog; PWWP, Pro-Trp-Trp-Pro; RAR, retinoic acid receptor; SAHA, suberoylanilide hydroxamic acid; SAM, S-adenosyl-methionine; SAR, structure–activity relationship; Sas, something about silencing protein; Sir2p, silent information regulator 2 protein; SIRT, sirtuin; STAT, signal transducers and activators of transcription; TET, ten-eleven translocation; Tip60, TAT-interacting protein 60; TSA, trichostatin A; TSG, tumor suppressor gene; UDG, uracil-DNA glycosylase; VPA, valproic acid. ⇑ Corresponding author. Address: Department of Pharmacy, College of Pharmacy, Seoul National University, Building 20, Room 303, 1 Gwanak-ro, Gwanak-gu, Seoul 151742, Republic of Korea. Tel.: +82 2 880 8919; fax: +82 2 880 2490. E-mail address: [email protected] (M. Diederich). http://dx.doi.org/10.1016/j.canlet.2014.06.005 0304-3835/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

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them are from micro-organisms and plants with terrestrial origins. For instance, plant-derived compounds are widely used as antitumor agents such a vincristine and vinblastine from Catharanthus roseus, paclitaxel from Taxus brevifolia, etoposide from Podophyllum peltatum while bleomycin, daunomycin and doxorubicin are bacterial products [32]. Nonetheless, oceans, covering over 70% of the Earth’s surface, contain an extensive biodiversity due to a tremendous variety of habitats housing marine plants, animals, and micro-organisms well adapted to their environment. Oceans represent undoubtedly a unique cradle of pharmacologically active new chemical structures, whose clinical potential remains largely unexplored. Recently, marine compounds were shown to regulate most hallmarks and enabling characteristics of cancer [140]. In particular, related to cancer drug discovery cell death [47] and inflammatory [46,49,51] cell signaling pathways were studied in detail. Interestingly, photosynthetic marine organisms account as important sources for compounds with anti-cancer activity [48]. Accumulating evidence clearly established that, besides genetic lesions, epigenetic alterations including DNA methylation, histone modifications and micro-RNAs (miRNAs) are driving all steps of carcinogenesis and play a critical role in initiation, development and maintenance of the tumor phenotype

[45,80,135,137,138]. The term ‘epigenetics’ refers to changes in gene expression independent of DNA sequence alterations. DNA methylation, histone modifications and small RNA-mediated gene silencing are tightly associated mechanisms involved in the regulation of gene expression [91]. Noteworthy, unlike genetic modifications, epigenetic ones are potentially reversible; this specific feature make epigenetic effectors an attractive target for anticancer treatments. Over the past years, epigenetic drugs (i.e. compounds targeting epigenetic mechanisms) discovery has expended very rapidly and many structures were identified as epigenetically active agents; however, only a restricted number of molecules have been clinically approved as epigenetic antineoplastic drugs, and a relatively small number are undergoing clinical trials (Table 1) [141]. In this context, epigenetic drug research is seeking for novel lead structures to develop more effective therapeutical agents. Considering that the marine ecosystem represents a largely unexplored source of molecular scaffolds; marine micro-organisms, plants, and animals recently emerged as a promising resource of potent bioactive drug candidates for anti-cancer therapy. Thus, in this review, we focus on epigenetically active marine-derived compounds displaying anti-cancer activities.

Table 1 Selected epigenetic drugs under clinical evaluation in cancer. The information related to clinical trials were retrieved from the following web site: http://clinicaltrials.gov/. When a compound is from natural origin, the common source is indicated. Targeted activity

Class of compound

Name

Comments

References

DNMT

Nucleosides analogues

5-aza-20 -deoxycytidine (Decitabine, DacogenÒ) Azacytidine (VidazaÒ)

FDA-approved for myelodysplastic syndromes; incorporated into DNA and blocks DNMT1 FDA-approved for myelodysplastic syndromes; incorporated into DNA (and RNA) and blocks DNMT1 5-aza-20 -deoxycytidine pro-drug From curcuma; decreases DNMT1 expression From green tea; decreases DNMT expression From soy; decreases DNMT activity and expression From parsley, celery; DNMT inhibitor Initially used in the treatment of hypertension, DNMT inhibitor

[78]

Natural

HAT

Small molecule Natural

HDAC

Benzamides

Cyclic peptides Depsipepides Hydroxamates

Short-chain fatty acids

Others

HMT

SG-110 Curcumin EGCG Genistein Luteolin Hydralazine Curcumin Quercetin CI-994 (Tacedinaline) MGCD0103 (Mocetinostat) MS-275 (Entinostat) None in clinical trial FK228 (Romidepsin) CHR-3996 ITF2357 (Givinostat) JNJ-16241199 (R306465) JNJ-26481585 (Quisinostat) LBH-589 (Panobinostat) NVP-LAQ824 (Dacinostat) PCI-24781 (CRA-024781) PXD101 (Belinostat) SAHA (Vorinostat) SB939 AN-9 (Pivanex, pivaloyloxymethyl butyrate) Butyrate Sodium 4-phenylbutyrate VPA 3,3-Diindolylmethane CUDC-101 Genistein Phenethyl isothiocyanate Resveratrol Suramin E7438

[90] [153] [101] [41] [1] [40] [31]

From curcuma; inhibits HAT (p300) From onion, broccoli, berries; sirtuin activator Inhibits HDAC1 and 2 Inhibits HDAC1, 2, 3 and 11 Inhibits class I HDACs

[28] [71] [92] [52] [134]

FDA-approved; from the bacteria Chromobacterium Violaceum; inhibits class I HDACs Inhibits class I HDACs Inhibits class I and II HDACs Inhibits class I HDACs Inhibits class I and II HDACs Inhibits non-sirtuin HDACs Inhibits class I and II HDACs Inhibits class I and IIb HDACs Inhibits non-sirtuin HDACs FDA-approved, inhibits non-sirtuin HDACs Inhibits non-sirtuin HDACs Inhibits Class I, IIa and IV

[54] [8] [53] [6] [158] [129] [21] [20] [126] [128] [131] [38]

From gut fermentation of dietary fibers; inhibits Class I, IIa and IV Inhibits HDACs Inhibits Class I and IIa Digestive product of indole-3-carbinol found in cruciferous vegetables; inhibits total HDAC activity, downregulation of class I HDACs Inhibits HDACs From soy; inhibits non-sirtuin HDACs and increases HAT activity From cruciferous vegetables; inhibits non-sirtuin HDACs From grape; sirtuin activator Inhibits SIRT1, 2 and 5 Inhibits EZH2

[33] [123] [65] [13] [93] [103] [162] [42] [154] [88]

DNMT: DNA methyltransferase, EGCG: epigallocatechin gallate, HAT: histone acetyltransferase, HDAC: histone deacetylase, SAHA: suberoylanilide hydroxamic acid, SIRT: sirtuin, VPA: valproic acid.

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Fig. 1. Overview of marine-derived compounds targeting epigenetic alterations involved in tumor suppressor gene silencing in cancer. Epigenetic alterations by silencing the expression and therefore the functions of tumor suppressor genes contribute to carcinogenesis. These epimutations include increased promoter methylation in CpG island regions of gene promoters associated with enrichment of histone repressive marks such as methylated H3K9 and H3K27 and a decrease of active histone marks including histone acetylated H3 and H4 and methylated H3K4. These modifications are mediated by the concert action of several enzymatic activities including: DNA methyltransferase (DNMT), histone acetyltransferase (HAT), sirtuin (SIRT) and non-sirtuin histone (HDAC), histone demethylase (HDM) and histone methyltransferase (HMT) activities. Epigenetically active marine-derived compounds are reported.

Epigenetic alterations in cancer Epigenetic marks by regulating chromatin structure and transcription can switch genes on and off and control which ones are transcribed to control cellular functions (Fig. 1). Alteration of DNA methylation patterns was the first epigenetic mark to be tightly link with carcinogenesis and to be responsible of altered gene expression by the mean of tumor suppressor gene (TSG) silencing [43,135]. DNA methylation in cancer In human, DNA methylation consists in the covalent addition of a methyl group on cytosine residues (5’-position of the pyrimidine ring) within CpG dinucleotides, resulting in the formation of 5-methylcytosines (5mC). The reaction is catalyzed by the family of DNA methyl transferases (DNMTs) using the cofactor S-adenosyl-methionine (SAM) as a methyl donor. Among this family, DNMT1 is denoted as the maintenance DNMT, as it owns the capability to conserve methylation patterns through DNA replication, due to its preference to hemi-methylated substrates. DNMT3A and 3B are mainly involved in de novo DNA methylation. Therefore, these enzymatic activities act in concert to establish and maintain heritable genomic methylation patterns [39]. So far, there is no evidence for the existence of a DNA demethylase activity that could catalyze DNA demethylation in a one-step reaction. However, DNA repair and oxidative pathways linked to the particular and unique chemical biology of cytosine could result in DNA demethylation [109]. This pathway is controlled by ten-eleven translocation (TET) and activation-induced deaminase (AID)/ apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) – family of cytidine deaminases (see for review [16,150]). TET1, 2, 3 are 2-oxoglutarate- and Fe(II)-dependent enzymes capable of converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and then further to 5-formylcytosine and 5-carboxylcytosine by successive oxidative steps. 5mC and 5hmC are deaminated by the AID/APOBEC family members

to generate 5-methyluracil and 5-hydroxymethyluracil, respectively. These various cytosine derivatives are further targeted by the uracil-DNA glycosylase (UDG) family of base excision repair (BER) glycosylases leading to cytosine replacement and DNA demethylation. In cancer cells, the alteration affecting DNA methylation the most thoroughly investigated is DNA hypermethylation. This epimutation corresponds to increased methylation at specific CpG dinucleotides that are usually unmethylated in healthy individuals. DNA hypermethylation occurs mainly at CpG islands, which correspond to GC-rich DNA regions of 200 bp to 4 kb-length with a GC content of at least 55% and a ratio of observed/statistically expected CG frequencies of greater than 0.6. CpG islands are found in about 60% of all genes, near promoter and exogenic regions [127]. Remarkably, a majority of cancer subtypes exhibit DNA hypermethylation at specific TSGs leading to their transcriptional repression. Examples of genes silenced by promoter hypermethylation include mutL homolog 1 (MLH1), retinoic acid receptor (RAR)-b and cyclin-dependent kinase (CDK) inhibitor genes (p16CDKN2A and p15CDKN2B) that are frequently methylated across various tumor subtypes. Moreover, genes such as glutathione S-transferase pi (GSTP)1, are more specifically silenced in certain cancer subtypes, progressive methylation being a hallmark of prostate cancer [39,45,81]. In cancer, local DNA hypermethylation is associated to global genomic DNA hypomethylation of highly repeated DNA sequences such as long interspersed element (LINE)-1 and certain target genes such as claudin (CLDN)4, maelstrom (MAEL), long non-coding (lnc)RNA H19/insulin-like growth factor (IGF)2 responsible for chromosomal instability and oncogenic activation, respectively [36,138]. Histone modifications and cancer In eukaryotes, DNA is packaged with histone and non-histone proteins into a higher-order structure of chromatin. Histones are targeted by multiple post-translational modifications including

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acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, citrullination, ADP-ribosylation b-N-acetylglucosamination or deamination. Altogether these modifications are regulating chromatin structure and activity [91,136]. The best-characterized modifications within histone tails are acetylation of lysine and methylation of arginine and lysine residues. The acetylation/deacetylation processes are governed by histone acetyl transferases (HATs) and histone deacetylases (HDACs), respectively. Similarly, methylation/demethylation reactions are catalyzed by histone methyltransferase (HMTs) and histone demethylases (HDMs), respectively. Noteworthy, acetylation exists only as a single addition, while multiple methylation levels (i.e. mono-, di-, and tri-methylation) can occur on the same residue [61]. HDAC isoenzymes are subdivided in four classes. Class I is composed of HDAC1, 2, 3 and 8, that are mainly located in the nucleus. Class II is further subdivided in subclass IIa with HDAC4, 5, 7 and 9; and subclass IIb with HDAC6 and 10. HDAC11 belongs to class IV. Class III, also called sirtuins, contains seven members, SIRT1-7. All members of HDAC class I, II and IV are zinc-dependent enzymes whereas, sirtuins use nicotinamide adenine dinucleotide (NAD)+ as a cofactor. All HATS use acetyl-coenzyme A as an acetyl donor and are classified in five families from which three have been extensively studied: the p300/CBP family, the Gcn5-related N-acetyltransferase (GNAT) family including the general control (GC)N5 and P300/CBP-associated factor (PCAF) and the MYST (for the founding members of this family: MOZ, Ybf2/Sas3, Sas2 and Tip60) family [58]. Notably, HDACs not only regulate the acetylation status of histone but also a myriad of other proteins. For instance, HDAC6 and SIRT2 target a-tubulin regulating microtubule stability [73]. The stability, subcellular localization and transcriptional activity of many transcription factors (e.g. GATA, NF-jB, STAT) are also regulated by acetylation [50,142]. Interestingly, SIRT1/2 regulate the acetylation of additional proteins such as p53, an important regulator of apoptosis, DNA repair, cell cycle arrest and metabolism [73]; forkhead box (FOX)O transcription factors, key regulators of cell fate [94]; and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a), a transcriptional co-activator that regulates mitochondrial biogenesis and functions [157]. The HMT family comprises a large number of enzymes using SAM as a cofactor, subdivided in SET-domain-containing proteins and DOT1-like proteins that target lysines, and protein arginine N-methyltransferase (PRMT) that target arginines (see for review [61]). HDMs were more recently identified and represent also a large group of enzymes subdivided in two classes: the flavin adenine dinucleotide (FAD)-dependent monoamine oxidase family and the both iron- and a-ketoglutarate-dependent dioxygenase jumonji (jmj) C-domain-containing proteins (see for review [61]). Similarly to HDACs/HATs, HDMs and HMTs target histone and non-histone proteins. Besides these writers and erasers of the epigenetic code, a third category of proteins emerged and plays an increasingly important role in epigenetically controlled gene expression. These proteins are termed readers of the epigenetic code without having the capacity to modify post-translation modifications of epigenetic targets. Accordingly, compound regulators of bromodomain-containing proteins, methyl-lysine- and/or methyl-arginine-binding domain-containing proteins including tudor domains, malignant brain tumor (MBT) domains, chromodomains and Pro-Trp-TrpPro motif (PWWP) domains as well as plant homeodomain (PHD)-containing proteins become interesting targets for pharmaceutically active compounds [5]. Altogether, the activity of these seven families of enzymes regulates gene expression and therefore is implicated in many cellular processes. Consequently, it is well founded that alterations of

185

histone modifications patterns or the altered assessment of the epigenetic code by regulatory ‘‘readers proteins’’ are tightly associated to tumorigenesis [34,125] and thus future druggable targets. miRNAs in cancer miRNAs are small non-coding (nc)RNAs of 19–25 nucleotides in length that post-transcriptionally regulate mRNA expression levels. miRNAs bind sequences located essentially in 50 and 30 untranslated regions of target genes degrading mRNA or blocking translation [80]. miRNAs are probably targeting more than half of all coding genes and largely contribute to regulating gene expression. A growing body of evidence suggests that deregulation of miRNA expression patterns is associated to tumor development [45,80,125]. These altered miRNA expression profiles may result from alterations of other epigenetic marks targeting miRNA genes or mutations affecting proteins involved in miRNA biogenesis and processing [80,125]. Besides small regulatory RNAs, lncRNAs attract increasing interest for anti-cancer therapy. LncRNAs are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that do not encode proteins. This family includes intronic as well as intergenic ncRNAs (lincRNAs). Although their role is still under investigation, removal of these ncRNAs is often associated with functional consequences. Remarkably, lncRNAs interact with proteins as well as with RNA or DNA [108]. Conversely, lncRNAs are tightly coordinated to produce an integrated regulatory effect and are emerging as master regulators of chromatin states by coordinating the role of writers, erasers and readers. For instance, the lincRNA HOXA transcript at the distal tip (HOTTIP) modulates the activity of the WDR5-MLL complex, in which the WD40-repeat protein WDR5 binds the mixed-lineage, leukemia (MLL) complex to activate its H3K4 HMT activity leading to the subsequent activation of targeted genes [35]. Another example demonstrating that lncRNA regulates chromatin remodeling and gene transcription is represented by the phosphatase and tensin homolog (PTEN) pseudogen PTENP1, which encodes two antisense RNA transcripts, a and b. The a isoform can recruit DNMT3A, the polycomb group protein EZH2 and the HMT G9A to PTEN promoter and repress its transcription [35]. This is just few examples of how lncRNAs can regulate epigenetic mechanisms and transcription (for review see [35,96]). Accordingly, deregulation of lncRNA expression profiles appears to be involved in tumorigenesis and may account as future druggable targets [108]. Anti-cancer epigenetic drugs Deregulation of the epigenetic machinery and aberrant epigenetic marks are together a common hallmark of cancer. These findings have been used as a driving force for the development of pharmacological inhibitors for epigenetic-based anti-cancer therapies (Table 1). In this context two nucleosides analogues able to inhibit DNMT activities (DNMTi), 5-azacytidine and 20 -deoxy-5-azacytidine, were approved by the FDA for the treatment of myelodysplastic syndromes. Treatments with such molecules can lead to TSG re-expression associated with cycle perturbation, induction of senescence, autophagy, differentiation and apoptosis leading to impaired cell proliferation and tumor regression [23,45,139,141]. The success of these two molecules prompted researchers to generate new derivatives with a better pharmacokinetic profile. Many molecules have been generated but so far only SG-110 is undergoing clinical evaluation [62,141]. Non-nucleoside DNMTi may represent a less toxic alternative to DNMTi that get incorporated into DNA. This class includes both synthetic and naturally occurring molecules; however, they usually display low potency and/or

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selectivity for DNMTs, and their mechanisms of inhibition are usually not fully understood [62,141]. Among chromatin modifying enzymes, HDACs have received the most attention as anti-cancer targets. Accordingly, several dozen of naturally occurring and synthetic HDAC inhibitors (HDACi) have been reported to date, which include benzamides, cyclic peptides, depsipeptides, hydroxamates and short fatty acids. These agents share structure similarities allowing to defining a HDAC pharmacophore consisting of a metal-binding moiety that interacts with the catalytic zinc ion, a hydrophobic linker region that mimics the substrate’s lysine chain and a cap that blocks the access of the substrate to the active site. Two HDACi namely suberoylanilide hydroxamic acid (SAHA, vorinostat, ZolinzaÒ) and FK228 (Romidepsin, IstodaxÒ) have been FDA-approved for the treatment of cutaneous T-cell lymphoma. SAHA is a synthetic derivative of trichostatin A (TSA, see below 4.16.), which displays similar biological properties to its parent compound; however, it is a more potent pan-HDACi with less toxicity against normal cells and side effects leading to its approval [29,141]. FK228 is so far the only epigenetic drug from natural origin to receive FDA approval. This depsipeptide acts as a prodrug from which the disulfide bond is reduced in vivo to reveal butenylthiol, which is implicated in class I HDAC inhibition. Despite potent activity against a broad range of tumor cells, FK228 displays serious cardiac side effects, which may limit its clinical use [105,141]. Remarkably, besides FDA-approved compounds and the family of HDACi there is very limited number of epigenetic drugs in clinical trials (Table 1). Marine and marine-derived compounds with anti-cancer activities acting as epigenetic modulators In the past few years, an increasing number of epigenetic modulators with marine origins were reported (Fig. 1). So far, there is no HAT or HDM inhibitor of marine origin reported and the vast majority of epigenetic modulators identified are HDAC inhibitors. Below we discuss marine-derived drugs with epigenetic activities displaying anti-cancer properties (Table 2 and Fig. 2). 1386A 1386A is a compound isolated from a mangrove fungus with the same name collected in the South China Sea. This compound displays cytotoxic effects (IC50 of 17.1 lM after 48 h of exposure) in human breast MCF-7 cancer cells leading to a time- and dosedependent inhibition of cell growth [151]. Authors have shown that MCF-7 cells exposed for 48 h to the IC50 concentration of 1386A display 45 miRNAs differentially expressed. Target prediction revealed that altered miRNAs potentially target several oncogenes and TSGs linked to cancer development, progression and metastasis that could explain the anti-cancer properties of this drug [151]. Further investigations are required to confirm these data and decipher the mechanism(s) of action of this new drug. Azumamides Nakao et al. were the first group to report the extraction, purification, structure determination and biological evaluation of five new and unusual cyclic tetrapeptides, named azumamides A-E (1–5), isolated form the Japanese marine sponge Mycale izuensis [111]. These molecules consist of four non-ribosomal amino acid residues, among which three are a-amino acids of the D-series (D-Ala, D-Phe, D-Val, D-Tyr), while the fourth one is a unique b-amino acid assigned as (Z)-(2S,3R)-3-amino-2-methyl-5-nonene-dioic acid, 9-amide in azumamides A (1), B (2) and D (4),

and as (Z)-(2S,3R)-3-amino-2-methyl-5-nonen-dioic acid in azumamides C (3) and E (5) [74]. Azumamides A-E (1–5) were first identified as in vitro inhibitors of total HDAC activity with IC50 values ranging from 0.045 to 1.3 lM using human chronic myeloid leukemia K-562 crude cell lysates. Accordingly, azumamide A (1) increases histone acetylation in K-562 cells in a concentration-dependent manner from 0.19 to 19 lM and induces cytotoxic effects in human colon cancer WiDr cells and K-562 cells with IC50 values of 5.8 and 4.5 lM, respectively [111]. Surprisingly, later it was demonstrated that only azumamides B (2), C (3) and E (5) were in vitro HDACi with IC50 values in the low micromolar range using HeLa (human cervix carcinoma) nuclear extracts and class I HDACs (mainly the isoenzymes 1 and 4) isolated from human embryonic kidney 293T cells. Furthermore, in these studies, derivative E (5) was the most potent compound due to its carboxylic acid warhead [104,110,163], which has a better affinity for zinc than an amide group (found in azumamides A (1), B (2), D (4)) based on the model of pharmacophore inhibition of non-sirtuin HDACs [141,142]. In another study, using two concentrations of compounds (5 and 50 lM) and recombinant human HDACs, it was shown that azumamide C (3), bearing a carboxylic acid moiety, was more potent against HDAC activities than derivative E (5) [159]. These discrepancies might be explained by differences in compound purity in both natural and synthetic compounds as well as by the type of assay utilized. Remarkably, azumamide E (5) is the only compound able to promote the expression of the CDK inhibitor p21 with an EC1000 value of 17.0 lM in mouse induced pluripotent stem cells [110]; a well-accepted marker induced by HDACi, which is inhibiting cell cycle progression [141,142]. The anti-cancer effect of azuzamide A (1) was associated to anti-angiogenic properties at 19 lM using a mouse in vitro model of vascular organization [111]. In another study, using the same experimental model, the same group demonstrated that azumamide E (5) displayed even more potent anti-angiogenic properties starting as low as 0.19 lM [110]. Various synthetic route of azumamides A (1) [74,159,163] and E (5) [22,74,159,163] were published, while so far only one synthetic route of azumamides B-D (2–4) was reported [159]. These studies have generated various analogues useful to assess azumamide SAR towards HDAC activities. These studies revealed that the b-amino acid residue is essential for the HDAC inhibitory activity of azumamides. Among analogues two molecules displayed more potent HDAC inhibitory activities: azumamide E-SAA, a sugar amino acid derivative analogue, and one in which the carboxylic warhead is replaced by a hydroxamic one, but these compounds were not further investigated in cells [22,163]. Bispyridinium alkaloids Pyridine alkaloids are a group of nitrogen-containing secondary metabolites very common in marine sponges, where they have anti-microbial properties. Oku et al. identified a group of structurally related macrocyclic bispyridinium alkaloids called cyclostellettamines A (6) and G (7), and dehydrocyclostellettamine D (8) and E (9) able to inhibit HDAC activity from K-562 cells. These cyclostellettamines were isolated from a marine sponge of the genus Xestospongia collected in Japan waters [117]. However, their HDAC inhibitory activity is rather weak (IC50 = 17–80 lM) compared to their cytotoxic potential (IC50 = 0.6–11.0 lM) against human cervix carcinoma HeLa, mouse leukemia P388 and rat fibroblast 3Y1 cell lines [117]. This difference suggests the existence of additional target(s) of these compounds mediating their cytotoxic properties. Pérez-Balado et al. reported a synthetic route to natural cyclostellettamines A-L and dehydrocyclostellettamines D (9) and E (10) using as the key step a microwave-mediated macrocyclic

Table 2 Marine epigenetic modulators. The structures of the after mentioned compounds are reported in Fig. 2. Compound

Chemical class

Source

References

[151]

The

Modulates miRNA expression profile in human breast cancer MCF-7 cells1: " miR-7, -21, 181b, -200c, -203, -638, -654-5p, -663, -1246, -1826 ; miR-25, -93, -125, -150, -182, -320 family, -1308, -let7 family In vitro2 HDACi, increases histone acetylation In vitro HDACi, class I HDACi In vitro HDACi, class I HDACi In vitro HDACi In vitro HDACi, class I HDACi, increases p21 expression In vitro HDACi, increases histone acetylation

[104,110,111] [104,110,111] [104,110,111] [104,110,111] [104,110,111] [117,121]

The

In vitro HDACi

[117]

The

In vitro HDACi

[117]

The

In vitro HDACi

[117]

Modulates miRNA expression profile inhuman lung cancer A-549 cells1: " miR-638 and -923

[26,27]

Suruga Bay, Japan

In vitro HMTi (G9a)

[148]

Suruga Bay, Japan

In vitro HMTi (G9a)

[148]

Suruga Bay, Japan

In vitro HMTi (G9a)

[148]

South coast of Curacao Key Largo, Florida Keys, USA US Virgin islands

In vitro HDAC1i In vitro HDACi, class I HDACi, increases histone acetylation

[82] [15,17,68,169]

Padana Nahua passage, Papua New Guinea

In vitro HMTi (SETD8)

[165]

Yanuca Island, Fiji, Melanesia Yanuca Island, Fiji, Melanesia Papua New Guinea Madagascar Papua New Guinea Madagascar Papua New Guinea Madagascar Papua New Guinea Madagascar Papua New Guinea Madagascar Papua New Guinea Madagascar Papua New Guinea andMadagascar Papua New Guinea Madagascar

In vitro DNMTi

[56,106]

In vitro DNMTi

[56,106]

and

In vitro DNMTi, In vitro HDACi

[124]

and

In vitro DNMTi, In vitro HDACi

[124]

and

In vitro DNMTi, In vitro HDACi

[124]

and

In vitro HDACi

[124]

and

In vitro HDACi

[124]

and

In vitro HDACi

[124]

In vitro HDACi

[124]

In vitro HDACi

[124]

Name

Location

1386A

Structure not available

Fungus

1386A

South China Sea

Azumamide A (1) Azumamide B (2) Azumamide C (3) Azumamide D (4) Azumamide E (5) Cyclostellettamine A (6)

Cyclic peptide Cyclic peptide Cyclic peptide Cyclic peptide Cyclic peptide Bispyridinium alkaloid

Sponge Sponge Sponge Sponge Sponge Sponge

Cyclostellettamine G (7)

Bispyridinium alkaloid

Sponge

Dehydrocyclostellettamine D (8)

Bispyridinium alkaloid

Sponge

Dehydrocyclostellettamine E (9)

Bispyridinium alkaloid

Sponge

Bostrycin (10)

Anthraquinone

Fungus

Japan waters Japan waters Japan waters Japan waters Japan waters Shishijima Island, Amakusa Islands, Southern Japan Shishijima Island, Amakusa Islands, Southern Japan Shishijima Island, Amakusa Islands, Southern Japan Shishijima Island, Amakusa Islands, Southern Japan South China Sea

Gliotoxin G (15)

Sulfur-containing toxin

Fungus

5a,6-didehydrogliotoxin (12) Gliotoxin (13)

Sulfur-containing toxin

Fungus

Sulfur-containing toxin

Fungus

Gymnochrome E (14) Largazole (16)

Phenanthroperylenequinone Depsipeptide

Crinoid Bacteria

Mycale izuensis Mycale izuensis Mycale izuensis Mycale izuensis Mycale izuensis Genus Xestospongia (Haliclona sp.) Genus Xestospongia (Haliclona sp.) Genus Xestospongia (Haliclona sp.) Genus Xestospongia (Haliclona sp.) Nigrospora sp. (No. 1403) Penicillium sp. (strain JMF034) Penicillium sp. (strain JMF034) Penicillium sp. (strain JMF034) Holopus rangii Genus Symploca

Microsporin A (17)

Cyclic peptide

Fungus

Nahuoic acid A (18)

Polyketide

Bacteria

Peyssonenyne A (19)

Fatty acid

Algae

Peyssonenyne B (20)

Fatty acid

Algae

Psammaplin A (21)

3-Bromotyrosine derivative

Sponge

Bisaprasin

3-Bromotyrosine derivative

Sponge

Psammaplin G (22)

3-Bromotyrosine derivative

Sponge

Psammaplin B (23)

3-Bromotyrosine derivative

Sponge

Psammaplin D (24)

3-Bromotyrosine derivative

Sponge

Psammaplin E (25)

3-Bromotyrosine derivative

Sponge

Psammaplin F (26)

3-Bromotyrosine derivative

Sponge

Psammaplin H (27)

3-Bromotyrosine derivative

Sponge

Microsporum gypseum sp. Streptomyces sp. (isolate RJA2928) Peyssonnelia caulifera Peyssonnelia caulifera Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea Pseudoceratina purpurea

and

[63]

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Epigenetic target(s) and mechanism(s)

Organism

In vitro HDAC1i Takara Island, Japan

[70]

In vitro HDAC1i Takara Island, Japan

[70]

In vitro HDAC1i Takara Island, Japan

[70]

In vitro HDAC1i Takara Island, Japan

[70]

[29,70,170] In vitro HDACi, non-sirtuin HDACi, increases protein acetylation and increases p21 expression

Trichostatin analogue

Bostrycin (10) a natural tetrahydroanthraquinone pigment isolated from several marine-derived fungus collected from the mangrove of South China Sea: Nigrospora sp. (No. 1403), Xylaria sp. (2508) [26,72]; and coral reef of Manado (Indonesia): Aspergillus sp. (strain 05F16) [168]. Bostrycin (10) displays cytotoxic properties in various human cancer models including lung A-549, breast MCF-7 and MDA-MB435, liver HepG2, and colon HCT-116 cell lines with IC50 values between 2.2 and 7.7 lM after 48 h of treatment. Compared to the immortalized human breast epithelial cell line MCF-10A, bostrycin (10) has a 2- to 7-fold selectivity against cancer cell lines [26,27]. Furthermore, 10–30 lM of this compound inhibits proliferation and induces the expression of the CDK inhibitor p27, G0/G1 cell cycle arrest and apoptosis in human lung carcinoma A-549 cells by down-regulating the PI3K/AKT pathway [27]. Finally, Chen et al. investigated miRNA expression profile in A-549 cells exposed to 10 lM bostrycin (10) for 72 h and found 54 mi-RNA differentially expressed with miR-638 and -923 being the most upregulated [27].

DNMTi: DNA methyltransferase inhibitor, HDACi: histone deacetylase inhibitor, SIRT: sirtuin. 1 The most up-and down-regulated micro-RNAs (mi-RNAs). 2 In vitro means determined by cell-free biochemical assay.

Bacteria

Trichostatin analogue

JBIR-111 (39)

Bacteria

Trichostatin analogue

JBIR-110 (38)

Bacteria

Trichostatin analogue Trichostatic acid (36)

JBIR-109 (37)

Bacteria

Hydroxamate Trichostatin A (35)

Bacteria

[66] In vitro SIRT1i and SIRT2i

Tanikely Island, Madagascar Takara Island, Japan Bacteria Dilactone Tanikolide dimer (34)

[24] ; miR-200c South China Sea Anthraquinone

Fungus

ring-closing metathesis of precursors bispyridinium dienes followed by catalytic hydrogenation [121]. For most compounds and precursors, authors systematically investigated their effect on HDAC activity as well as p21 protein expression, histone H3 and a-tubulin acetylation, cell cycle distribution, granulocytic differentiation, and apoptosis in human histiocytic lymphoma U-937 cells using 1 or 5 lM of each compounds. Interestingly, acyclic bispyridinium diene precursors are globally more potent HDACi and display increased biological activities compared to the natural compounds. For instance, the open-chain precursor 10b is a HDAC1-selective inhibitor inducing histone H3 acetylation and p21 expression and 10a is a HDAC subclass IIa-selective inhibitor inducing G1 cell cycle accumulation without affecting protein acetylation. Nevertheless, all open-chain bispyridinium dienes induce apoptosis after 30 h of treatment at the concentration of 5 lM [121]. Bostrycin

SZ-685C (33)

[3] In vitro SIRT1i and SIRT2i Bacteria Streptosetin A (32)

[119] In vitro HDAC2i Cytotoxin Santacruzamate A (31)

Bacteria

In vitro HDACi 3-Bromotyrosine derivative Psammaplin J (29)

Sponge

[124] 3-Bromotyrosine derivative Psammaplin I (28)

Sponge

In vitro HDACi

Epigenetic target(s) and mechanism(s) Organism

Source Chemical class Compound

Table 2 (continued)

[124]

Papua New Guinea and Madagascar Papua New Guinea and Madagascar Coiba National Park, Panama San Francisco Bay, USA

Pseudoceratina purpurea Pseudoceratina purpurea Genus Symploca sp. Streptomyces violaceusniger Nigrospora sp. (No. 1403) Lyngbya majuscula Streptomyces angustmycinicus Streptomyces angustmycinicus Streptomyces angustmycinicus Streptomyces angustmycinicus Streptomyces angustmycinicus

References Location

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Name

188

Gliotoxins Several gliotoxins were isolated from the fungus Penicillium sp. strain JMF034, obtained from deep-sea sediments of Japan. Spectroscopic data revealed five already known compounds and two new metabolites. The known compounds were identified as bis(dethio)bis(methylthio)gliotoxin already characterized in the fungus Gliocladium deliquescens [87], bis(dethio)bis-(methylthio)5a,6-didehydrogliotoxin and gliotoxin G (11) found initially in the fungus Gliocladium virens [86], 5a,6-didehydrogliotoxin (12) isolated from the fungus Gliocladium flavofuscum [7], and gliotoxin (13) already characterized in the fungus Dichotomomyces cejpii [79]. The new compounds were identified as bis(dethio)-10amethylthio-3a-deoxy-3,3a-didehydrogliotoxin and 6-deoxy-5a, 6-didehydrogliotoxin [148]. Although all compounds exhibited cytotoxic activity against P388 murine leukemia cells (IC50 values between 0.02 and 3.4 lM after 96 h of treatment), only compounds containing a disulfide bond, namely gliotoxin G (11), 5a,6-didehydrogliotoxin (12) and gliotoxin (13) showed potent in vitro inhibitory activity against the recombinant H3K9 HMT G9a (IC50 = 2.1–6.4 lM) without affecting the H3K4 HMT SET7/9 [148]. Gymnochrome E Gymnochrome E (14) is a cytotoxic brominated phenanthroperylenequinone pigments isolated from the deep-water crinoid Holopus rangii. Gymnochrome E (14) inhibits the proliferation of

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189

Fig. 2. Structures of natural marine-derived epigenetic modulators. The structure of compound 1386A reported in Table 2 is not available. *Synthetic compound.

Fig. 2 (continued)

the multi-drug-resistant ovarian NCI/ADR-Res cancer cell line (IC50 = 3.5 lM) but had no effect at a concentration of 6.4 lM on pancreatic carcinoma PANC-1 or human colorectal adenocarcinoma DLD-1 cell lines. Furthermore, gymnochrome E (14) also inhibits HDAC1 activity with an IC50 of 10.9 lM [82]. Remarkably, gymnochrome F (15), a co-purified and structurally related

compound to gymnochrome E (14), lacks HDAC inhibitory activity and significant toxicity against PANC-1, NCI/ADR-Res and DLD-1 tumor cell lines at a concentration of 5.2 lM [82]. Gymnochrome E (14) is also an inhibitor of the binding of the anti-apoptotic member of the BCL-2 family, MCL-1, to the pro-apoptotic BCL-2 member BAK (IC50 = 3.3 lM), which regulates apoptosis once released [82].

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Fig. 2 (continued)

Largazole and its analogues Largazole (16) is a highly functionalized macrocyclic depsipeptide originally isolated from a cyanobacterium of the genus Symploca [152]. Largazole (16) was trivially named based on its location of collection, Key Largo (Florida Keys, USA), as well as the presence two azole-like moieties: an a-methylcysteine-derived thiazoline coupled to a thiazole. These characteristic chemical features are embedded in an unusual strained 16-membered macrocycle possessing a remarkable scaffold including a caprylic acid-derived thioester, which is rarely encountered in natural products. The structure of largazole (16) contains also one nonmodified L-valine amino acid [68,152]. Largazole (16) was initially revealed to display very potent growth-inhibitory potential against various cancer cell models (GI50: 7.7–55 nM), whereas non-transformed fibroblasts epithelial cells were inhibited at much higher doses (GI50: 122–480 nM). The selectivity of largazole (16) for cancer cells was unmatched by other natural drugs tested including paclitaxel, actinomycin D and doxorubicin [112,152]. Later these data were extended to the National Cancer Institute’s 60 cell line system showing that largazole (16) has a highly effective growth-inhibitory potential against many cell lines with a mean GI50 value of 17 nM (1.6–320 nM). Accordingly, largazole (16) displays cytotoxic effects at much higher concentrations (mean LD50 = 18.6 lM) [99]. The remarkable selectivity of largazole (16) against cancer cells prompts the scientific chemistry community to establish synthetic routes of this compound for extensive biological evaluation of its mechanisms of action [14,15,17,18,59,112,116,132,143,147,160, 166,169,173]. The different synthetic routes have been extensively discussed in several reviews [68,97,114].

Largazole (16) is a depsipeptide with the intriguing presence of a thioester functionality expected to be swiftly hydrolyzed through cellular metabolism to generate the corresponding thiol form of largazole as observed with three other naturally occurring depsipeptides: FR901375, FK228, and spiruchostatin A, which are all well-established HDACi [141]. Based on these features, Luesch et al. were not only the first group to propose a total synthesis of largazole and some analogues including the thiol form, but also the first to demonstrate its HDAC inhibitory properties [169]. Indeed, largazole inhibits both in vitro and in cellulo total HDAC activity (IC50 around 50 nM) and induces histone H3 acetylation in a concentration-dependent manner starting about 1–10 nM without affecting a-tubulin acetylation. These findings were confirmed by latter studies that further demonstrate that largazole (16) displays class I selectivity profile [15,17,68,169]. A wide range of largazole analogues have been synthesized to modulate its structural scaffold focusing on the thioester linker region, the L-valine subunit, and the 4-methylthiazoline–thiazole subunit with the goal to deeply investigate the SAR of this compound [14,15,18,19,25,59,64,112,143,147,160,169,173]. These studies demonstrated that largazole (16) acts as a prodrug and the thiol form is the active metabolite, which is indispensable for both activities (i.e. HDAC inhibition and anti-proliferation). Accordingly, in vitro assay showed that the thiol form is a much more potent HDACi (IC50 in the picomolar range) [17]. Nonetheless, all these studies failed to identify largazole analogues with a more potent HDAC inhibitory activity than the parent compound. Unfortunately, several studies only investigated the effect of these derivatives on cell proliferation but not on HDAC activity or only on HDAC activity without testing the effect on protein acetylation. Nonetheless, altogether these studies suggest the importance of

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associated to a suppression of cell invasion in vitro and enhanced dexamethasone effects [95]. Besides its effect on HDAC activity, it was shown that largazole (16) acts as an ubiquitin E1 inhibitor (IC50 = 29 lM) that could account for its anti-cancer properties [155]. Microsporin A Microsporin A (17) is a cyclic tetrapeptide purified from the culture of the marine-derived fungus Microsporum gypseum sp. isolated from a sample of the bryozoan Bugula sp. collected in the US Virgin Islands [63]. This molecule is constituted of three amino acids with a L configuration, while the pipecolic acid present a D configuration. Notably, authors have reported that microsporin A (17) possesses a similar inhibitory activity than SAHA against in vitro total HDAC activity (IC50 values of 0.14 and 0.30 lM for microsporin A (17) and SAHA, respectively) and displays cytotoxic properties against human colon HCT-116 cancer cells (IC50 = 1.2 lM) as well as against the National Cancer Institute 60 cancer cell panel with a mean IC50 value of 2.7 lM [63]. These promising data require further investigations to determine whether the biological activity of microsporin A (17) is related to its HDAC inhibitory potential. Nahuoic acid A

Fig. 2 (continued)

positioning the thiol functionality at the right distance from the cyclic core and the necessity of the thiobutenyl group for its antiproliferative activity. Remarkably, L-valine can be replaced with L-alanine or glycine without drastic loss of HDAC inhibitory activity [14,169]. Furthermore, Cole et al. demonstrated that other L-amino acids might be used at this position as long as they do not perturb the overall conformation of the macrocyclic depsipeptide core [30]. However, by exchanging L-valine by L-tyrosine in largazole (16) enhanced its selectivity toward human cancer cells versus normal cells over 100-fold but authors did not test the effect on HDAC activity or protein acetylation [173]. Interestingly, the analogue 2-epi-largazole was less potent that largazole (16) on HDAC activity but about two times more cytotoxic on PC-3 and LNCaP prostate cancer cell lines [160]. Several studies have investigated the downstream effects of largazole (16) associated to decreased cancer cell proliferation. In human colon HCT116 cancer cells low concentrations (1–3.2 nM) of largazole (16) cause G1 cell cycle arrest, whereas higher concentrations (10 nM) lead to G2/M arrest. Higher concentrations (>10 nM) induce caspase activity and trigger apoptosis. Furthermore, largazole (16) induces several CDK inhibitors (p15, p19, p21, p57) and down-regulates CDK6 and cyclin D1 in NB4 and HCT116 cells [99,147]. In vivo, using a HCT116 xenograft mouse model, 5 mg/kg largazole (16) administrated by intraperitoneal injection induces protein acetylation and caspase activation leading to a reduction of tumor growth and volume [99]. Recently it was demonstrated that 125 nM largazole (16) have anti-fibrotic and anti-angiogenic properties both in vitro using hepatic stellate cells (HSCs) and in vivo using a mouse liver fibrotic model by inhibiting transforming growth factor-b and vascular endothelial growth factor signaling, while largazole (16) had no effect on normal hepatocytes. Remarkably, these effects are dependent of the HDAC inhibitory activity of largazole (16) [100]. Further studies demonstrate that 100 nM largazole up-regulates epigenetically-silence E cadherin gene and change its subcellular localization in breast cancers MDA-MB231 cells. These effects are

Nahuoic acid A (18) is a polyketide produced in culture by a bacteria Streptomyces sp. (isolate RJA2928) obtained from a tropical marine sediment near the Padana Nahua passage in Papua New Guinea. Interestingly, nahuoic acid A (18) is the first selective SAM-competitive inhibitor of the HMT SETD8 activity (IC50 = 6.8 lM) reported without affecting the activity of other HMTs such G9a, EHMT1, SETD7, SUV39H2, SUV420H1, SUV420H2, DOT1L, PRMT3, and PRMT5 and MLL complexes [165]. SETD8 is a HMT that plays a key role in the silencing of euchromatic genes by monomethylating histone H4 (lys 20) [61]. In addition, this enzyme represses p53 target genes by methylating p53 [144] and enhances cell proliferation by methylating PCNA [149]. In this context, since SETD8 is found overexpressed in various cancers [149], it might represent an interesting therapeutic target in cancer. Therefore, it would be interesting to investigate the effect of nahuoic acid A (18) on cancer cells and to evaluate the effect of this structure on HDAC activities since other polyketides were reported as HDACi [37,164]. Peyssonenynes Peyssonenynes A (19) and B (20) are x3 fatty acids possessing an unusual enediyne motif isolated from the Fijian red marine algae Peyssonnelia caulifera. They were identified as DNMTi using a bioassay-guided fractionation [106]. These compounds were initially reported to be geometric isomers at the acetoxyenediyne moiety; however, the full synthesis of these molecules coupled to extensive analysis of NMR and HPLC data revealed that peyssonenynes A (19) and B (20) are the sn-1,3 and sn-2 positional isomers at the glycerol moiety, respectively [56]. In the initial study, pure peyssonenynes A (19) and B (20) were shown to display comparable activities against purified DNMT1 enzyme in in vitro activity assay (IC50 values of 16 and 9 lM, respectively) [106]. However, using DNMT1 immunoprecipitated from K-562 cells, Garcia-Dominguez et al. demonstrated that the molecules, at the concentration of 50 lM, are more potent that the DNMTi RG108 but less potent than SGI-1027 [56], a potent non-nucleoside quinoline-based DNMTi [156]. However, it remains to determine whether these compounds induce DNA demethylation and to test their anti-cancer potential.

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A synthetic derivative of palmitic acid bearing the functional group diynone from the peyssonenyne natural products, called diynone 8, was reported in vitro to inhibit DNMT1 (30% of inhibition) and activate DNMT3A (a 2.5-fold increase) activities at the concentration of 50 lM. Furthermore, this compound induces differentiation and apoptosis in U-937 cells starting at the concentration of 5 lM. Intriguingly, diynone 8 is toxic to normal human and mouse fibroblasts, but not to immortalized human fibroblasts [57]. These findings would require more investigations. Psammaplins Psammaplin A (PsA, 21) is a symmetrical brominated tyrosine derived metabolite containing a disulfide linkage formed from the condensation of modified tyrosine and cysteine units. Psa was isolated for the first time in 1987 from an unidentified marine sponge [4], probably Thorectopsamma xana [133], from the pacific ocean around Guam island and from the sponge Psammaplinaplysilla sp. from pacific ocean around Tonga [130]. This metabolite was further found in other sponges collected in various places in pacific ocean including Aplysinella rhax from Fiji island waters [122], Pseudoceratina purpurea collected from around Papua New Guinea and Madagascar [124] and from a two-sponge association, Poecillastra sp. and Jaspis sp. collected from Korean waters [77]. A dimer of PsA (21), bisaprasin, has also been isolated from T. xana [133] and P. purpurea [124] and many other psammaplin family members have been isolated of marine sponge of the Verongida order rich of such metabolites [122,124,130]. PsA (21) was reported to display broad-spectrum anti-cancer activities. This drug inhibits cell growth and possesses cytotoxic properties in the low micromolar range against multiple human cell lines from lung, ovarian, skin, colon endometrial and breast cancer subtypes, P-glycoprotein-over-expressing multidrug resistant cell lines, and murine and human leukemia cell models [2,55,76,83,107,146]. Notably, PsA (21) radiosensitizes lung cancer A-549 and glioblastoma U-373MG cell lines probably due to an inhibition of DNA repair [85]. The underlying mechanism of PsA (21) anti-cancer properties may rely on its potency to modulate various human enzymes that regulate DNA replication, transcription, differentiation, proliferation, apoptosis, tumor invasion, and angiogenesis. For instance PsA (21) inhibits topoisomerase II [83], farnesyl protein transferase [145], leucine aminopeptidase [145], and polymerase a-primase [76] and activates peroxisome proliferator-activated receptor-c (PPARc) [107]. However, the in vitro inhibitory concentration against these targets is in the micromolar range. In contrast, it was reported that PsA (21), psammaplin G (22) and bisaprasin inhibit both HDAC and DNMT1 activities in vitro in the low nanomolar range, whereas psammaplins B (23), D-F (24–26) and H-J (27–29) were inhibiting only total HDAC activity [124]. Although the in vitro DNMT inhibitory activity of PsA (21) was later observed by another group [60], no DNMT1 inhibitory activity was reported in other studies [10,55]. Accordingly, no DNA demethylation has been observed in HCT-116 cells treated for 14 days with 1 lM PsA (21) [60]. These discrepancies might be related to variations in product purity, assay procedure or cell models. Further investigations of the HDAC inhibitory potential of this class of compounds point out that psammaplins A (21), B (23), E (25), and F (26) induce histone H3 acetylation at a concentration of 0.2 lM without affecting a-tubulin acetylation suggesting they are class I HDACi [84]. Conversely, at the same concentration PsA (21) increases p21 expression associated to cell cycle arrest [2]. Several chemistries starting for instance from tyrosine or phenylpyruvic acid derivatives or from aromatic aldehydes (to generate arylpyruvic acids) have been proposed to provide sufficient amounts for further investigations [11,60,69,115] and generated

many analogues allowing deep SAR against HDAC [9,12,55,67, 113,120]. These studies point out that PsA (21) acts as a prodrug that similarly to FK288 need to be reduced in its corresponding monomeric thiol form being the active molecule responsible of chelating the zinc ion in the active site of HDACs for their inhibition [10,55,84]. Furthermore, by replacing the a-(hydroxyimino)acyl units by a fluorescent 4-coumarinacetyl moiety, Hentschel et al. demonstrated that the disulfide is cleaved to the thiol probably before entering the nucleus [67]. UVI5008 (30) is probably one of the most intriguing PsA analogues as in addition to have increased class I HDAC and DNMT3A inhibitory potential this compound in which a 5-bromoindole unit in 4a replaces the o-bromophenol gained further inhibitory activity against SIRT1 and 2. This triple epigenetic regulator at a concentration of 5 lM increases histone, p53 and a-tubulin acetylation and promotes DNA demethylation in RARb and p16CDKN2A promoters and gene reactivation. Conversely, UVI5008 (30) displays strong anti-cancer properties in several cell lines derived from colon, breast, and prostate carcinomas (IC50 values ranging from 0.2 to 3.1 lM) as well as in vivo using a dose of 40 mg/kg in HCT116or MCF-7-xenografted mice and ex vivo using a concentration of 5 lM in acute myeloid leukemia (AML) blasts [113]. Santacruzamate A Santacruzamate A (31) is a cytotoxin isolated from a cyanobacteria of genus Symploca sp. collected from the Coiba National Park on the Pacific coast of Panama. Although santacruzamate A shares several structural features in common with the pan-HDACi suberoylanilide hydroxamic acid, it acts in vitro at picomolar level as a selective HDAC2 inhibitor [119]. This specificity for HDAC2 could be of interest for therapeutic purposes since the general lack of selectivity of common HDACi is believed to be responsible of many side effects [118]. Notably, santacruzamate A (31) induces cytotoxicity in colon HCT-116 colon cancer (IC50 = 29.4 lM) and cutaneous T-cell lymphoma HuT-78 (IC50 = 1.4 lM) cell lines without affecting the viability of human dermal fibroblasts (IC50 > 100 lM) [119]. Nevertheless, it remains to determine whether these effects are connected to HDAC inhibition in cells. Streptosetin A Amagata et al. identified a new class III HDAC inhibitor by screening a library composed of 506 extracts of marine-derived actinomycetes employing a HDAC-based yeast assay using an URA3 reporter gene embedded in the telomere region of the yeast chromosome, which is activated by inhibitors of the yeast homologue Sir2p to human SIRT1 [3]. Based on a bioassay-guided purification and extensive NMR study the new compound was designated as streptosetin A (32), a compound purified from Streptomyces violaceusniger found in a sediment sample collected in San Francisco Bay (USA). Further analysis revealed that streptosetin A (32) is an in vitro SIRT1 and 2 inhibitor at rather high doses (IC50 values of 3.7 and 4.5 mM, respectively) [3]. Nonetheless, the effect of this compound was not tested on cells. SZ-685C SZ-685C (33) is a marine anthraquinone purified from mangrove endophytic fungus (No. 1403) collected from the South China Sea [167]. This compound was reported to decrease proliferation in multiple cancer cell models including glioma, hepatoma, breast and prostate cancer cell lines (IC50 values ranged from 3.0 to 9.6 lM). Furthermore, this drug induces apoptosis in human breast

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cancer MCF-7 and MDA-MB-435 cells in a dose-dependent manner from 3.75 and 1.5 lM, respectively. Conversely, the intraperitoneal injection of 50 mg/kg SZ-685C (33) inhibits the growth of tumors formed by MDA-MB-435 cells xenografted in immunodeficient mice. It was suggested that SZ-685C (33) triggers apoptosis by suppressing Akt/FOXO pathway [167]. Later these data were confirmed by the investigation of Wang et al., showing that SZ-685C (33) displays pro-apoptotic activity in both radiosensitive and radioresistant human nasopharyngeal carcinoma CNE2 cells through miR-205-PTEN-Akt pathway [161]. Another study demonstrated that SZ-685C (33) induces apoptosis in MMQ pituitary tumor cells (IC50 = 13.2 lM) by down-regulating miR-200c, but showed less toxicity toward rat pituitary cells (IC50 = 49.1 lM) [24]. Tanikolide dimer Tanikolide dimer (34) is a dilactone isolated from the marine cyanobacteria Lyngbya majuscula collected near Tanikely Island, Madagascar [66]. Tanikolide dimer was co-purified with tanikolide seco acid using a human SIRT2 bioassay-guided approach. Further analysis revealed that only tanikolide dimer is a potent in vitro SIRT2 inhibitor (IC50 = 176 nM), about 200–300 fold more active than the well-characterized sirtuin inhibitor sirtinol [66]. Synthetic production of tanikolide dimer (34) and extensive chiral GC–MS approach revealed than the natural tanikolide dimer (34) is (5R, 50 R). Comparing naturally occurring tanikolide dimer (34) with other synthetic stereoisomers (5R-5’S, 5S-5S’), Gutierrez et al. observed that chirality does not matter and all three stereoisomers have similar potential to inhibit SIRT1 and 2 activities, with about 10-fold less potency against SIRT1 than SIRT2 [66]. Surprisingly, cytotoxicity assays revealed that tanikolide seco was moderately toxic to the human lung H-460 cell line at a concentration of 9.9 lM while tanikolide dimer (34) was inactive at 10 lM. This effect may suggest that tanikolide dimer (34) could be more promising in neuroprotection [172]. Trichostatins One of the best-characterized and first natural HDACi identified is TSA (35) [89,98]. TSA (35) is a natural hydroxamate originally isolated from a bacteria present in soil Streptomyces platensis but also found in other bacterial strains such as Streptomyces hygroscopicus Y-50 and Streptomyces sioyaensis [29,171]. More recently, TSA (35) was isolated from a culture of Streptomyces angustmycinicus found associated with a marine sponge collected from a mesopelagic area in Japan waters [70]. TSA (35) was initially reported as a potent inducer of differentiation in murine erythroleukemia Friend and RV133 cell lines. The maximum induction was obtained at 15 nM and 0.5 lM, respectively [171]. Later is was reported that TSA (35) inhibits cell cycle in G1 and G2 phases due to an increase of the expression of the CDK inhibitor p21 and can promote differentiation and apoptosis in various solid and non-solid tumors [29]. The anti-cancer properties of TSA (35) are believed to be due to increases histone acetylation as it selectively inhibits in vitro and in vivo the non-sirtuin HDAC enzymes [170]. Besides TSA (35), Hosoya et al. have isolated form the culture of the marine-derived bacteria S. angustmycinicus, trichostatic acid (36) and three other trichostatin analogues: JBIR-109 (37), JBIR110 (38), and JBIR-111 (39) [70]. However, these molecules are over 1000-fold weaker HDAC1 inhibitors than TSA in vitro (IC50 values against recombinant HDAC1 of 35–39 are 0.012, 73, 48, 74 and 57 lM, respectively); probably because of the lack of hydroxamate functionality, which is of major importance for TSA activity against HDACs [170].

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Critical considerations and future perspectives Considering the increasing opportunities for epigenetic modulators and marine-derived compounds in anti-cancer therapy, the development of marine-derived epigenetic modulators is of considerable interest. Hence, this review has summarized current knowledge on the anti-cancer potential of naturally occurring marine compounds capable of affecting several epigenetic mechanisms, including DNA methylation, acetylation and methylation of histones, and miRNA effects on gene expression. Nevertheless, so far, there is no HAT or HDM inhibitor reported and most of the epigenetically active molecules are targeting HDAC activities. More importantly, most HDACi are reported to be pan-non-sirtuin-HDACi or selective against HDAC1, 2, 3, 8, 11, which are structurally related HDACs. This lack of selectivity might not always be totally correct and could simply represent the consequence of a lack of characterization of the HDAC inhibitory activity profiling of considered compounds. Nevertheless, such investigations are critical to find new scaffolds being more selective against HDAC isoenzymes, which could represent valuable tools for mechanistic studies as well as anti-cancer therapy. Remarkably, there is no marine or marine-derived compound in clinical trial with well-established epigenetic properties. This lack of compound in clinical trials is probably translating the fact that, to date, the number of epigenetic modulators identified from marine ecosystems is rather limited in comparison to molecules form terrestrial ecosystems, which are mainly plant- and micro-organism-derived compounds. One of the reasons seems most likely because compounds from marine origins were under investigated as potential modulators of epigenetic effectors. However, over the past few years a number of structures have emerged as interesting families of molecules displaying promising anti-cancer properties. Among these agents, one of the most promising is largazole, which presents one of the most interesting HDAC inhibitory profile identified yet associated to a highly effective growthinhibitory potential in a low nanomolar range. Two other families of molecules that sound really attractive are azumamides and psammaplins. Indeed, the structure variations among the members of these groups are associated to various HDAC inhibitory profiles and cellular outcomes. These findings may provide new critical data for structure–activity relationship studies and the development of better HDACi with improved specificity and anti-cancer spectrum displaying reduced side effects. Furthermore, psammaplins as potential dual epigenetic inhibitors may represent lead compounds for further anti-cancer drug development. Similarly, the identification of TSA analogs provides valuable information about structures involved in HDAC inhibition. In this context, it is reasonable to imagine that new TSA analogues could be identified in the future with an improved therapeutic potential compared to TSA, which displays a significant toxicity against normal cells and side effects. Furthermore, considering the important pool of new chemical scaffolds hold by marine ecosystems and the continuously growing capacity of exploration of the marine world coupled to an increasing interest for epigenetic mechanisms and targeted therapies, there is no doubt that new compounds targeting either well-established as well as newly identified epigenetic targets such as TET proteins will be discovered and potentially turned into new anti-cancer drugs. Nonetheless, the design of more specific and targeted screening procedures would probably favor the discovery of novel and potent marine pharmacophores against epigenetic effectors. The classical epigenetic anti-cancer drugs are commonly targeting the activity of epigenetic writers or erasers. However, targeting epigenetic readers, which translate the histone code and additional epigenetic marks constituting the chromatin structure into biolog-

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ical functions could represent an attractive alternative of intervention by providing a more targeted approach and finer tuning of chromatin regulation that targeting in an unspecific manner HDACs for instance. In this context, modulators of specific epigenetic protein–protein interactions would probably provide new mechanistic insights into chromatin regulation and unravel new therapeutic opportunities. There are only few examples of such compounds in the literature including for instance a series of synthetic 4-(pyrrolidin-1-yl)piperidine amine analogues that inhibit selectively the binding of lethal 3 malignant brain tumor-like protein (L3MBTL)1 and L3MBTL3, two methyl-lysine reader proteins of H4K20me1-2 marks [75]; 4-acyl pyrrole derivative and JQ1 that inhibit bromodomain containing proteins, which are acetyl-lysine mark readers [44,102]. Nonetheless, the number of potent inhibitors of the various histone binding modules and proteins binding methylated DNA (i.e. methyl CpG binding proteins (MBDs)) is rather limited. Accordingly, using the diversity of scaffolds offered by the marine world combined to more thorough analyses should allow the identification of new potent pharmacophores of these readers. Although the results of anti-cancer strategies based on the use of various epigenetic drugs alone or in combinatory treatments sound very promising, these approaches require a careful control investigation of the impact of such interventions for each classes of epigenetic effectors targeted. Indeed, the remodeling of the epigenetic landscape may engender adverse side effects such as promoting the expression of proto-oncogenes and potentially reprogram any healthy cells including stem cells, which would be more harm than good. Nevertheless, we are convinced that the development of such therapeutic interventions has a large potential to be further included in the therapeutic arsenal of clinicians. Conflict of Interest Authors declare no conflict of interest. Acknowledgements MS is supported by a ‘‘Waxweiler grant for cancer prevention research’’ from the Action Lions ‘‘Vaincre le Cancer’’. This work was supported by Télévie Luxembourg, the «Recherche Cancer et Sang» foundation and «Recherches Scientifiques Luxembourg» association. The authors thank «Een Häerz fir Kriibskrank Kanner» association and the Action Lions ‘‘Vaincre le Cancer’’ for generous support. MD is supported by the NRF by the MEST of Korea for Tumor Microenvironment GCRC 2012-0001184 grant. References [1] M. Adjakly, R. Bosviel, N. Rabiau, J.P. Boiteux, Y.J. Bignon, L. Guy, D. BernardGallon, DNA methylation and soy phytoestrogens: quantitative study in DU145 and PC-3 human prostate cancer cell lines, Epigenomics 3 (2011) 795–803. [2] M.Y. Ahn, J.H. Jung, Y.J. Na, H.S. Kim, A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells, Gynecol. Oncol. 108 (2008) 27–33. [3] T. Amagata, J. Xiao, Y.P. Chen, N. Holsopple, A.G. Oliver, T. Gokey, A.B. Guliaev, K. Minoura, Creation of an HDAC-based yeast screening method for evaluation of marine-derived actinomycetes: discovery of streptosetin A, J. Nat. Prod. 75 (2012) 2193–2199. [4] L. Arabshahi, F.J. Schmitz, Brominated tyrosine metabolites from an unidentified sponge, J. Org. Chem. 52 (1987) 3584–3586. [5] C.H. Arrowsmith, C. Bountra, P.V. Fish, K. Lee, M. Schapira, Epigenetic protein families: a new frontier for drug discovery, Nat. Rev. Drug Discov. 11 (2012) 384–400. [6] J. Arts, P. Angibaud, A. Marien, W. Floren, B. Janssens, P. King, J. van Dun, L. Janssen, T. Geerts, R.W. Tuman, D.L. Johnson, L. Andries, M. Jung, M. Janicot, K. van Emelen, R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies, Br. J. Cancer 97 (2007) 1344–1353.

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Epigenetic modulators from "The Big Blue": a treasure to fight against cancer.

Cancer remains a major public health problem in our society. The development of potent novel anti-cancer drugs selective for tumor cells is therefore ...
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