toxins Review Ellagitannins in Cancer Chemoprevention and Therapy Tariq Ismail 1, Cinzia Calcabrini 2,3, Anna Rita Diaz 2, Carmela Fimognari 3, Eleonora Turrini 3, Elena Catanzaro 3, Saeed Akhtar 1 and Piero Sestili 2,* 1 Institute of Food Science & Nutrition, Faculty of Agricultural Sciences and Technology, Bahauddin Zakariya University, Bosan Road, Multan 60800, Punjab, Pakistan; [email protected] (T.I.); [email protected] (S.A.) 2 Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via I Maggetti 26, 61029 Urbino (PU), Italy; [email protected] 3 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini (RN), Italy; [email protected] (C.C.); carmela.fi[email protected] (C.F.); [email protected] (E.T.); [email protected] (E.C.) * Correspondence: [email protected]; Tel.: +39-(0)-722-303-414 Academic Editor: Jia-You Fang Received: 31 March 2016; Accepted: 9 May 2016; Published: 13 May 2016 Abstract: It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties. Keywords: ellagitannins; phytochemicals; cancer; chemoprevention; cancer therapy; safety 1. Introduction Despite the enormous efforts of the scientific and medical community, cancer still represents the second leading cause of death and is nearly becoming the leading one in the elderly [1]. It is estimated that, due to demographic changes alone, in the next 15 years the number of new cancer cases will increase by 70% worldwide [2]. The lack of effective diagnostic tools for early detection of several tumors, the limited treatment options for patients with advanced stages of cancer, and the onset of multiple drug resistance favor poor prognosis and high mortality rates. The significant, but still unsatisfactory, improvement of survival, the severe toxicity profile, and the high costs characterizing many current anticancer therapies clearly show that a threshold in terms of clinical benefit and patients’ tolerance has been reached. Thus, the identification and development of innovative, preventive as well as therapeutic strategies to contrast cancer-associated morbidity and mortality are urgently needed. Epidemiological, preclinical, and clinical studies have generally concluded that a diet rich in phytochemicals can reduce the risk of cancer [2,3]. Due to their pleiotropism which includes Toxins 2016, 8, 151; doi:10.3390/toxins8050151 www.mdpi.com/journal/toxins Toxins 2016, 8, 151 2 of 22 Toxins 2016, 8, 151 2 of 21 antioxidant, anti-inflammatory, and antiproliferative activities as well as modulatory effects on subcellular signaling pathways, phytochemicals from edible fruits and vegetables are recognized as subcellular signaling pathways, phytochemicals from edible fruits and vegetables are recognized an effective option to counteract cancer incidence and mortality [3–5]. Plants constitute a primary and as an effective option to counteract cancer incidence and mortality [3–5]. Plants constitute a large source of various chemical compounds including alkaloids, flavonoids, phenolics, tannins, primary and large source of various chemical compounds including alkaloids, flavonoids, phenolics, tocopherols, triterpenes, and isothiocyanates. Ellagitannins (ET) are an important class of tannins, tocopherols, triterpenes, and isothiocyanates. Ellagitannins (ET) are an important class of phytochemicals contained in a number of edible plants and fruits recommended by the traditional phytochemicals contained in a number of edible plants and fruits recommended by the traditional medicine of a variety of cultures, both in the developing and developed countries, to treat common medicine of a variety of cultures, both in the developing and developed countries, to treat common health problems. ET biological and nutraceutical potential has received increasing attention over the health problems. ET biological and nutraceutical potential has received increasing attention over the last several decades. ET exert multiple and clinically‐valuable activities [4], and among them the last several decades. ET exert multiple and clinically-valuable activities [4], and among them the chemopreventive, anticarcinogenic, and antiproliferative activities are being receiving growing chemopreventive, anticarcinogenic, and antiproliferative activities are being receiving growing interest interest and attention (Figure 1). and attention (Figure1). Figure 1. Fruits containing ET with chemopreventive, anticarcinogenic, and antiproliferative activities. Figure 1. Fruits containing ET with chemopreventive, anticarcinogenic, and antiproliferative activities. 2. Dietary Sources, Types, and Occurrence 2. DietaryET and Sources, their derivatives Types, and are Occurrence noticeably contained in edible seeds, nuts, and various fruits of nutritionalET and interests. their derivatives The structures are noticeably of relevant contained ETs and of in ellagic edible acid seeds, are nuts, shown and in Figurevarious2. fruits A wide of varietynutritional of fresh interests. fruits The including structures berries, of relevant like raspberries, ETs and blackof ellagic raspberries, acid are strawberries,shown in Figure pomegranate, 2. A wide longan,variety andof driedfresh nuts,fruits are including renowned forberries, their amplelike raspberries, polyphenols concentrationblack raspberries, in the formstrawberries, of ET [5]. Fivepomegranate, species of longan, berries and including dried nuts, raspberry, are renowned strawberry, for cloudberry, their ample rose polyphenols hip, and concentration sea buckthorn in were the identifiedform of ET by [5]. Koponen Five specieset al. of,[6 berries] as significant including carrier raspberry, of ET strawberry, in a range of cloudberry, 1–330 mg perrose 100 hip, g and of fruit. sea Sanguiinbuckthorn H-6 were and identified lambertianin by Koponen C were reportedet al., [6] fromas significant Glen Ample carrier raspberries of ET in a and range Scottish-grown of 1–330 mg redper raspberries,100 g of fruit. along Sanguiin with H some‐6 and trace lambertianin levels of ellagic C were acid reported [7,8]. Blackberries from Glen Ample (fruit and raspberries seeds) have and beenScottish reported‐grown for red a rangeraspberries, of ET includingalong with pedunculagin, some trace levels casuarictin, of ellagic sanguiin acid [7,8]. H-6 Blackberries (lambertianin (fruit A), and lambertianinseeds) have been (C and reported D) [9 –for11]. a Pomegranaterange of ET including and various pedunculagin, fractions of casuarictin, the fruit are sanguiin known H for‐6 their(lambertianin cancer chemopreventive A), and lambertianin properties (C and owing D) [9–11]. to their Pomegranate unique phenolics and various composition fractions in of the the form fruit ofare ET, known which for include their cancer punicalagin, chemopreventive punicalin, properties granatin A, owing granatin to their B, tellimagrandin unique phenolics I, pedunculagin, composition corilagin,in the form gallagic of ET, acid, which ellagic include acid, punicalagin, and casuarinin punicalin, [12]. granatin A, granatin B, tellimagrandin I, pedunculagin, corilagin, gallagic acid, ellagic acid, and casuarinin [12]. Toxins 2016, 8, 151 3 of 22 Toxins 2016, 8, 151 3 of 21 FigureFigure 2.2. StructuresStructures of of ellagic ellagic acid acid and and of of three three major major and and representative representative ellagitannins. ellagitannins. EA, ellagicEA, ellagic acid; PED,acid; PED, pedunculagin; pedunculagin; PUN, PUN, punicalagin; punicalagin; SAN, SAN, sanguiin sanguiin H-6. H‐6. ET,ET, predominatelypredominately thosethose isolatedisolated fromfrom pomegranatepomegranate (e.g.,(e.g., punicalagin),punicalagin), have gainedgained aa widewide popularitypopularity asas preventivepreventive andand therapeutictherapeutic ethnopharmacologicalethnopharmacological approaches for cancer treatment. However,However, aa lotlot moremore hashas beenbeen addedadded toto this class of compounds from fruits other than pomegranate, includingincluding raspberries,raspberries, blueberries,blueberries, strawberries,strawberries, muscadinemuscadine grapes,grapes, andand longanlongan [[7,13–18].7,13–18]. MajorMajor phenolicphenolic fractionsfractions recoveredrecovered fromfrom longanlongan includeinclude gallicgallic acid,acid, ellagicellagic acid,acid, andand corilagin,corilagin, muchmuch moremore concentratedconcentrated in thethe seedseed segmentsegment asas comparedcompared toto thethe fruitfruit pulppulp andand peelpeel [[17].17]. GoodGood