http://informahealthcare.com/rst ISSN: 1079-9893 (print), 1532-4281 (electronic) J Recept Signal Transduct Res, Early Online: 1–9 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2014.931431

REVIEW ARTICLE

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Mangiferin in cancer chemoprevention and treatment: pharmacokinetics and molecular targets Peramaiyan Rajendran1, Thamaraiselvan Rengarajan1, Natarajan Nandakumar2, H. Divya3, and Ikuo Nishigaki1 1

NPO – International Laboratory of Biochemistry, Uchide, Nakagawa-ku, Nagoya, Japan, 2Department of Microbiology, Immunology and Genetics, Ben Gurion University of the Negev, Beer Sheva, Israel, and 3Department of Biochemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India Abstract

Keywords

A variety of bioactive food components have been shown to modulate inflammatory responses and to attenuate carcinogenesis. Polyphenols isolated several years ago from various medicinal plants now seem to have a prominent role in the prevention and therapy of a variety of ailments. Mangiferin, a unique, important, and highly investigated polyphenol, has attracted much attention of late for its potential as a chemopreventive and chemotherapeutic agent against various types of cancer. Mangiferin has been shown to target multiple proinflammatory transcription factors, cell- cycle proteins, growth factors, kinases, cytokines, chemokines, adhesion molecules, and inflammatory enzymes. These targets can potentially mediate the chemopreventive and therapeutic effects of mangiferin by inhibiting the initiation, promotion, and metastasis of cancer. This review not only summarizes the diverse molecular targets of mangiferin, but also gives the results of various preclinical studies that have been performed in the last decade with this promising polyphenol.

Cancer, chemoprevention, inflammation, mangiferin, polyphenol

Introduction A natural product is a chemical composite or ingredient produced by a living organism. It is found in nature and typically has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design. A natural product can be considered as such even if it can be prepared by total synthesis. These small molecules provide the source or stimulus for the majority of Food and Drug Administration (FDA)-approved agents and continue to be one of the major sources of inspiration for future drug discovery. In particular, these compounds are significant in the treatment of lifethreatening conditions (1). Epidemiological studies suggest that high dietary intake of polyphenols is associated with a decreased risk of a range of diseases including cardiovascular disease (CVD), specific forms of cancer (2,3) and neurodegenerative diseases (4). In particular, a group of polyphenols known as flavonoids have been strongly linked with beneficial effects in many human, animal, and in vitro studies (5). With respect to cardiovascular health, flavonoids may alter lipid metabolism (6), inhibit low-density lipoprotein (LDL) oxidation (7), reduce the formation of atherosclerotic lesions (8), inhibit platelet

Address for correspondence: Ikuo Nishigaki, NPO – International Laboratory of Biochemistry, 1-166, Uchide, Nakagawa-ku, Nagoya 454-0926, Japan. Tel: 81 5236 11601. E-mail: [email protected]

History Received 6 May 2014 Accepted 2 June 2014 Published online 1 July 2014

aggregation (9), decrease the expression of vascular celladhesion molecule (10), improve endothelial function (11), and reduce blood pressure (12). However, flavonoids have also been shown to exert beneficial cognitive effects, to reverse specific age-related neurodegeneration (13), and to exert a variety of anticarcinogenic effects, including induction of apoptosis in tumor cells (14,15), inhibition of cancer cell proliferation (16) and prevention of angiogenesis and invasion by tumor cells (17). Over the past 15 years, researchers and food manufacturers have become increasingly interested in polyphenols. The chief reason for this interest is the recognition of the antioxidant properties of polyphenols, their great abundance in our diet, and their probable role in the prevention of various diseases associated with oxidative stress, such as cancer and cardiovascular and neurodegenerative diseases (18). Furthermore, polyphenols, which constitute the active substances found in many medicinal plants, modulate the activity of a wide range of enzymes and cell receptors (19). In this way, in addition to having antioxidant properties, polyphenols have several other specific biological actions that are as yet poorly understood. Two aims of research are to establish evidence for the effects of polyphenol consumption on health and to identify which of the hundreds of existing polyphenols are likely to provide the greatest protection in the context of preventive nutrition. If these objectives are to be attained, it is first essential to determine the nature and distribution of these compounds in

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our diet. Such knowledge will allow evaluation of polyphenol intake and enable epidemiologic analysis that will in turn provide an understanding of the relationship between the intake of these substances and the risk of development of various diseases. Furthermore, not all polyphenols are absorbed with equal efficacy. They are extensively metabolized by intestinal and hepatic enzymes and by the intestinal microflora. Knowledge of the bioavailability and metabolism of the various polyphenols is necessary to evaluate their biological activity within target tissues (20). A number of medicinal plants and herbs, such as Silybum marianum, Terminalia arjuna, Cajanus indicus, Phyllanthus niruri, Pithecellobium dulce (21), in India and other parts of the world are natural sources of antioxidants that act as the first line of defense against free radical-induced damage and are considered to be important in maintaining optimum health and happiness. These natural substances are used for the treatment of hepatic, renal, and other organ disorders. Polyphenolic compounds and flavonoids are abundant in fruits, vegetables, tea, and wine and are usually recognized to have powerful antioxidant properties (22). In connection with these plants and herbs, another important medicinal plant available throughout the world is Mangifera indica L. It belongs to the family Anacardiaceae and is the source of many natural xanthones, polyphenols, etc. Earlier, isolated mangiferin from its bark was determined to constitute 2-C-b-D-gluco-pyranosyl-1, 3,6,7-tetrahydroxyxanthone (C19H18O11; Mw, 422.35; melting point, anhydrous 271uC (23), a natural C-glucoside xanthone (24). A number of studies reported that mangiferin has a broad range of therapeutic uses. It possesses antioxidant (25–27), antidiarrhea (28), antidyslipidemic (29), antidiabetic (30), antiallergic (31), antibacterial (32), antiHIV (33), and anticancer (34) activities. Besides, it is also used as an analgesic, immunomodulatory (35) and immunostimulatory (36) agent. Cancer, currently the second leading cause of death in the western world, may outrank cardiovascular diseases in the US and other developed countries in a few decades (37–39). Deaths from cancer worldwide are projected to continue rising, with an estimated 13.1 million deaths in 2030 (40). The recent progress in molecular biology and pharmacology has increased the likelihood that cancer prevention, either primary or secondary, will rely increasingly on interventions collectively termed ‘‘chemoprevention’’. Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The progression towards invasive cancer is characterized by the accumulation of mutations and increased proliferation. Because carcinogenesis is a multistage process and often has a latency of many years or decades, there is considerable opportunity for intervention. Molecular advances have led to the identification of genetic lesions and other cellular components that may be involved in the initiation and progression of malignancies and constitute potential targets for chemoprevention. As most cancers are likely to be associated with mutagens and/or mitogens, focusing on compounds that may inhibit or reverse the effects of either of these related molecules may be crucial in the search for chemotherapeutic agents. Chemoprevention not only has obvious elements in common with chemotherapy, but also distinct differences. Thus, chemoprevention focuses

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on reducing the incidence of cancer and is related to classical epidemiology; whereas chemotherapy focuses on prognosis and is related to clinical epidemiology. Chemotherapy can be either systemic or, in certain cases, localized; whereas chemoprevention is almost always systemic. Last, chemotherapy is applied to seriously ill patients, for whom sideeffects, even serious ones, may be acceptable’ whereas a chemopreventive agent is generally administered to healthy people for whom serious side effects are unacceptable. Several models have been developed to outline the pathways through which carcinogenesis may occur. These include the Vogelstein model for colon cancer (41), as well as models for cancer of the head and neck (42,43), brain (44), bladder (45,46), and lung (47). Valid models of cancer progression facilitate the identification of intermediate biomarkers. By serving as surrogate end-points, such markers are pivotal in identifying chemopreventive agents. The use of early markers of carcinogenesis allows chemopreventive studies to focus on stage arrest or reversion following treatment (48). Many classes of agents have shown promise as chemopreventive agents. These include antiestrogens, antiinflammatories, antioxidants, and other diet-derived agents. Here, we discuss in detail the potential of mangiferin as a chemopreventive and anticancer drug and its reported beneficial effects based on preclinical investigations. Also, we highlight in detail various mechanisms by which mangiferin modulates cellular transcription factors, growth factor receptors, inflammatory cytokines, and other major intracellular molecular targets that regulate cancer cell proliferation, apoptosis, invasion, metastasis, and angiogenesis.

Isolation and chemical properties of mangiferin Initial research studies and the published work on the extraction, isolation, and chemical composition of mangiferin indicated that it is a C-glucopyranoside of 1,3,6,7-tetrahydroxyxanthone (49). However, the point of attachment of the glucose residue to the xanthone nucleus remained to be resolved. Ramanathan and Seshadri (50) isolated crystalline mangiferin from the bark of M. indica. They further examined the composition of mangiferin by synthesizing its methyl ether derivatives and subsequently subjecting them to methods such as methylation and periodic acid oxidation. They concluded that glucose was linked to the second position of the xanthone nucleus of mangiferin. El Sissi and Saleh (51) quantitatively extracted mangiferin from the leaf material of M. indica. In their study on the composition of mangiferin they used degradation studies and ultraviolet spectrophotometric analysis. Paper chromatographic analysis resulted in characteristic Rf values for mangiferin in different mobile phases. When sprayed with different spray agents, mangiferin gave distinct and characteristic colors, such as green with ferric chloride (1% alcoholic), yellow with lead acetate (1% aqueous), and yellow with ammonia. Sissi and co-workers (51) reported the maximum absorption of mangiferin and also a characteristic bathochromic shift in the presence of aluminum chloride and sodium acetate. Phloroglucinol and 2,4,5-tri hydroxy benzoic acid were obtained as degradation products of mangiferin and KOH fusion at 260 for half an hour.

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The nuclear magnetic resonance studies and chemical degradation analysis of mangiferin by Haynes and Taylor (52) confirmed it to be 2-b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone, as had been suggested by Ramanathan and Seshadri (50). Mangiferin was successfully isolated from the stem bark of M. indica along with other polyphenolic components by El Sissi and El Ansari (53). They inferred that even in high concentration (10.1%), mangiferin had no influence on the amount of tannins absorbed by hide powder. El Ansari et al. (54) isolated and characterized mangiferin from an acetone extract of M. indica. Their results were confirmed by paper chromatographic analysis and chemical degradation studies. Bhatia et al. (55) isolated mangiferin from an alcoholic extract of the leaves and stem bark of M. indica. Further, they confirmed the composition of mangiferin through reductive hydrolysis with hydriodic acid and oxidation with ferric chloride. 1,3,6,7Tetrahydroxyxanthone and glucose were obtained as resultant products, confirming the constitution of mangiferin as previously suggested by Ramanathan et al. (50). The position of the linkage at C-2 was established by oxidizing mangiferin tri and tetra methyl ethers with periodate to obtain the corresponding a-hydroxy acetaldehydes of trimethoxy and tetramethoxy xanthones. The results were further confirmed by UV and IR spectral analysis. Nott and Roberts (56) also isolated mangiferin from the bark of M. indica. They further suggested chemical methods for confirming the point of attachment of the glucose residue to the xanthone nucleus. Their experimental work involved the alkali fusion of mangiferin and some of its derivatives. Bhatia and Seshadri (57) for the first time chemically synthesized mangiferin by reacting 1,3,6,7-tetrahydroxyxanthone with tetra-O-acetyla-D-glucopyranosyl bromide. Through the synthesis of mangiferin, Bhatia et al. (55) confirmed that the glucoside had the b-configuration. In an attempt to confirm the linkage between the sugar and aglycone of C-glycosyl compounds, Prox et al. (58) reported the mass spectrum of mangiferin and concluded that when the sugar was bound to the aromatic ring, the other substituents influenced the fragmentation in a characteristic manner. In another study, Chaudhuri and Ghosal (59) established the identity of mangiferin through chemical and mass spectral studies. Mangiferin was isolated from the bark of M. zeylanica by Herath et al. (60). Their ethanolic extract yielded mangiferin; and the paper chromatographic behavior and spectrophotometric analysis of it were identical with the data recorded for authentic mangiferin. Aritomi and Kawasaki (61) isolated a new xanthone Cglycoside named homomangiferin, co-existing with mangiferin. On the basis of chemical and spectral data it was formulated as 2-C-b-D-glucopyranosyl-3-methoxy-1,6,7-trihydroxyxanthone, i.e. 3-O-methylmangiferin. Later on, they also isolated isomangiferin from aerial parts of Anemarrhena asphodeloides (49). On the basis of their chemical and spectral data the structure was assigned as 4-C-b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone. Researching polyphenolics of M. indica, El Ansari et al. (62) simultaneously isolated 3 xanthones - mangiferin, isomangiferin, and homomangiferin – from this plant and identified these phenolic components by using UV spectral analysis, acid hydrolysis, chromatographic analysis, etc. Frahm and

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Chaudhuri (63) presented an analysis of 13C NMR chemical shifts of mangiferin. The additivity data provided by them could be applied for the structural elucidation of naturally occurring polysubstituted xanthones. Tanaka et al. (64) isolated mangiferin from the leaves of M. indica and characterized its structure on the basis of chemical and spectroscopic evidence. Furthermore, they also isolated a new xanthone, C-glucoside gallate, which was characterized as mangiferin-60 -O-gallate. Berardini et al. (49) isolated four xanthone C-glycosides from M. indica. These xanthone C-glycosides were subjected to high-performance liquid chromatography-electrospray ionization/mass spectrometry. On the basis of the resulting fragmentation pattern, they were identified as mangiferin and isomangiferin and their galloyl derivatives. Rojas-Hernandez et al. (65) tried to contribute to subsequent pharmacokinetic studies on mangiferin and also to understand its biological effects by subjecting mangiferin to UV and NMR spectral analysis and stability study in aqueous solution involving the determination of the pKa value of mangiferin. Most of the phytochemical studies conducted with regard to the structural elucidation and characterization of mangiferin have involved chemical methods such as used in degradation studies as well as spectrophotometric analytical techniques including UV, IR, NMR, mass spectroscopy. The authors are of the opinion that there exists a good correlation between traditional and folklore use of mangiferin and the results of the recent research studies on the same. Pharmacological evaluation in research studies conducted on mangiferin as well as on an extract of M. indica reveals the fact that mangiferin, being the major chemical and representative constituent of M. indica, exhibits pharmacological activities similar to those exhibited by the plant extract of M. indica itself. Mangiferin has prominent pharmacological actions corroborated by numerous research studies. Potential antiinflammatory, analgesic, antipyretic, antioxidant, immunomodulator, anti-tumor, antiviral, antihelmintic, antiallergic, antihistaminic, cardioprotective, anticholinergic, antiamoebic and antidiabetic effects have been found to be exerted by mangiferin (49).

Anticancer potential of mangiferin Decades of research have provided ample evidence that the polyphenols are multi-faceted in their molecular mechanism(s), as they modulate multiple targets and multiple pathways (66) (Figure 1). Numerous biochemical and pharmacological effects of mangiferin, including antiinflammatory, antioxidant, antiproliferative, anticancer, antimutagenic, antiartherosclerotic, antihypertensive, antileukemic, antiviral, and antidiabetic, have been reported previously (67). We will discuss the reported anticancer effects of mangiferin in brief below. In vitro anticancer effects of mangiferin Several inflammatory signaling cascades, including those involving nuclear factor-kB (NF-kB), as well as the expression of other survival signals such as extracellular signalregulated kinase 1/2, protein kinase B, and p38 mitogenactivated protein kinase, have been linked with different

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Figure 1. Oncogenic cascades maodulated by magniferin in tumor cells. These include a wide variety of transcription factors and modules involved in tumor cells proliferation, angiogenisis, metastasis and apostosis.

stages of cancer progression and are reported to regulate tumor proliferation, survival, invasion, metastasis, and angiogenesis (68). The transcription factor NF-kB is a key regulator of cellular events (69). NF-kB activation is often associated with chronic inflammation and tumorigenesis (70) as well as with tumor chemoresistance and radioresistance (71). Numerous publications have provided evidence that upregulated NF-kB activity leads to chronic inflammation, which has been causally linked to the development of several human diseases including cancer and have indicated that an understanding of the mechanisms of action of constitutive NF-kB should lead to the development of novel therapeutics for cancer treatment. Phosphorylation of IkB proteins by IkB kinases is a vital process that leads to NF-kB-DNA binding and transcriptional activation of target genes (72). Decades of research on natural product agents that inhibit or deregulate this pathway have provided ample evidence that numerous dietary constituents and nutraceuticals may have antiinflammatory and chemopreventive effects (66,72). In vitro studies using a variety of tumor cell lines have demonstrated the usefulness of mangiferin in chemoprevention and in the treatment of inflammation-driven disease (Table 1). Although mangiferin has been shown to prevent a variety of inflammation-associated diseases, the exact molecular mechanism is yet to be elucidated (91,92). Li et al. (75) demonstrated anticancer activity of mangiferin, as was evaluated in breast cancer cell line-based in vitro and in vivo models. Mangiferin treatment resulted in decreased cell viability and suppression of metastatic

Table 1. In vitro anticancer effects of mangiferin and its derivatives. Breast Carcinoma: [1] Immunosuppressive anti-tumor action. [2] Regulation of matrix metalloproteinases, epithelial-to-mesenchymal transition, and b-catenin signaling pathway. [3] Cytotoxicity, cell-cycle arrest, and apoptosis. [4] Suppression of activation of tumor necrosis factor Multiple myeloma: [1] Antiproliferation and apoptosis [2] Regulation of telomerase activity and cell cycle [3] Cell-cycle arrest Hepatocellular carcinoma: [1] Cytoprotection and antigenotoxic. [2] Chemoprevention [3] Induction of apoptosis and cell-cycle arrest [4] Induction of apoptosis and inhibition of proliferation Colon Carcinoma: [1] Increased Apoptosis and down-regulation of NFkB [2] Cytotoxicity Skin Carcinoma: [1] Suppression of solar UV-induced skin cancer by targeting ERKs [2] Inhibition of Akt Lung carcinoma: [1] Antitumor Activity [2] Inhibition of cell proliferation [3] Cell proliferation mechanism Ovarian Carcinoma [1] Anti tumor activity

(73) (74) (75) (76) (77) (78) (79) (80) (81) (82) (83) (84) (85) (86) (87) (88) (89) (90) (88)

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potential of breast cancer cells. Further mechanistic investigation revealed that mangiferin caused a decrease in matrix metalloproteinase (MMP)-7 and -9 activities, and a reversal of the epithelial–mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of the b-catenin pathway. Subsequent experiments showed that inhibiting this pathway might play a central role in mangiferin-induced anticancer activity through the modulation of MMP-7 and -9, and EMT. Consistent with these in vitro findings, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice, in which significantly decreased tumor volume, weight, and proliferation, and increased apoptosis, were obtained, along with lower expression of MMP-7 and -9, vimentin, and active b-catenin, and higher expression of E-cadherin (75). On the other hand, mangiferin-mediated down-regulation of NFkB showed potential for chemotherapeutic agent-mediated cell death, suggesting a role for mangiferin in combination therapy for cancer (89). In this study the mechanism of the anticancer action of oxaliplatin combined with mangiferin was investigated. MTT dose-response curves, trypan-blue staining, caspase-3 assays as well as DNA cell-cycle analyses were performed on HeLa, HT29, and MCF7 cancer cell lines, with and without the addition of 10 mg/ml mangiferin. The mitochondrial membrane potential, DNA fragmentation, resistance-induction studies, and NFkB assays were performed on HT29 cells only. The addition of 10 mg/ml mangiferin reduced oxaliplatin IC50 values in HT29 (3.4 fold) and HeLa (1.7 fold) cells in the MTT assay while reducing the intensity of trypan blue staining. This action was accompanied by increased activation of caspase-3 and DNA fragmentation and a delay in the S-phase of the cell cycle. Mitochondrial membrane permeabilization was not enhanced by the combination treatment. Mangiferin was shown to cause a reduction in NFkB activation in HT29 cells rendered resistant to oxaliplatin. This study (89) indicates that mangiferin in combination with oxaliplatin favors apoptotic cell death and thereby improves the efficacy of oxaliplatin in vitro. In addition, combination therapy with mangiferin may also counteract the development of resistance in cancer cell lines (89). Liu Hung and Chang Ho Ping (75) also studied Mangiferin to inhibit the A549 lung cancer cell proliferation and apoptosis, for in-depth research to provide anti-tumor mechanism Mangiferin experimental basis. Peng Zhi-Gang et al. (93) observed early stage of mangiferin -induced apoptosis was associated with cleavage (activation) of caspase-8, caspase-9, and caspase-3 and the proapoptotic protein Bid, Inhibitors of caspase-8 and caspase-9 markedly attenuated apoptosis, indicating the involvement of both extrinsic and intrinsic apoptotic pathways in K562 cells. Caspase-8 inhibition abrogated bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by mangiferin. Collectively, these results suggest a mechanistic basis for the potential use of mangiferin in the treatment and prevention of cancer. Mangiferin also K562 cells induced apoptosis may be through reduced BCR/ABL fusion protein P210, bcl-2 and sur-vivin mRNA gene expression and increased bax gene expression to achieve (93).

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Table 2. In vivo chemopreventive and anticancer effects of mangiferin. Natural Effects Lung Carcinoma [1] Immunomodulation [2] Chemoprevention [3] Modulation of oxidative stress and antioxidants [4] Enhanced expression of detoxification enzymes [5] Alteration of electron transport chain complexes and of key enzymes of the tricarboxylic acid cycle [6] Inhibition of polyamines Colon carcinoma [1] Regulation of matrix metalloproteinases, epithelial-to-mesenchymal transition, and b-catenin signaling pathway. [2] Inhibition of tumor growth Hepatocarcinoma [1] Potent cytotoxic effect [2] MPT-mediated apoptosis Breast carcinoma [1] Antitumor and immunostimulatory activities. [2] Regulation of matrix metalloproteinases, epithelial-to-mesenchymal transition, and b-catenin signaling pathway. Prostate cancer [1] Promotion of cell-cycle arrest [2] Inhibition of tumor growth Skin carcinoma [1] Suppress ion of cancer growth Stomach [1] Antiulcerogenic action

References (95) (96) (97) (98) (99) (100) (74) (33) (101) (102) (103) (74)

(104) (105) (106) (107)

Lvjian Zhen et al. (91) investigated mangiferin acute myeloid leukemia cell line HL-60 cell cycle distribution and cell cycle regulation of gene expression to further study the role of anti-leukemia mangiferin mechanism. Mangiferin role early in HL-60 cells can be induced by G2/M phase arrest, and increased HL-60 cells CDC2, CyclinB1, CyclinA, Wee1, CDC25C and Chk1mRNA expression levels of relevant; mangiferin HL-60 cells that induced G2/M phase arrest may be the anti-leukemia molecular mechanism of action (94). In vivo chemopreventive and anticancer activities of mangiferin Mangiferin has been reported to inhibit tumor growth in vivo in various animal models of cancer (Table 2). Treatment with mangiferin (50 mg/kg b.w.) for 6 weeks inhibited the growth of tumors in Swiss albino mice without having any significant effect on body weight, thus showing chemopreventive effects (98,99). The effect of pretreatment with 50 mg/kg b.w mangiferin was investigated by our group (100,101). We found that Swiss albino mice fed mangiferin in their diet for 5 weeks (weeks 2–6) exhibited delayed tumor development. Lung cancer-bearing animals revealed a loss of architecture and alveolar damage, as evidenced by hyperchromatic and irregular nuclei in the cells of the alveolar wall. Cancerbearing animals pre-treated with mangiferin exhibited reduced alveolar damage with a nearly normal architecture. Animals post-treated with mangiferin showed slightly reduced alveolar damage. Mice treated with mangiferin alone showed

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no appreciable change in lung histology from that of naı¨ve (control) animals (99). A study by Hongzhong Li (75) revealed that mangiferin induced a decrease in the expression of matrix metalloproteinase (MMP)-7 and -9, and caused a reversal of the epithelial–mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of the b-catenin pathway. Subsequent experiments showed that inhibiting the b-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and EMT (75). Consistent with these in vitro findings, the antitumor potential was also verified in mangiferin-treated MDA-MB-231-xenografted mice, in which tumor volume, weight, and proliferation were significantly decreased, and apoptosis was increased. In addition, the treated animals showed lower expression of MMP-7 and -9, vimentin and active b-catenin and higher expression of E-cadherin (75). Taken together, this study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. Another study investigated the effects of mangiferin on the expression by activated mouse macrophages of diverse genes related to the NF-nB signaling pathway, in which study a DNA hybridization array containing 96 NF-nB-related genes was used (109). Its effect on cytokine levels was also examined by using a cytokine protein array. Mangiferin significantly inhibited the expression of the following: two genes of the Rel/NF-nB/InB family, RelA and RelB (¼I-rel), indicating an inhibitory effect on NFnB-mediated signal transduction; TNF receptor-associated factor 6 (Traf6), indicating probable blockage of activation of the NF-nB pathway by lipopolysaccharide (LPS), tumor necrosis factor (TNF) or interleukin 1 (IL-1); other proteins involved in responses to TNF and in apoptotic pathways triggered by DNA damage, including the TNF receptor (TNF-R) (108), the TNF-receptor-associated death domain (TRADD), and the receptor-interacting protein (RIP); the extracellular ligand IL-1a, again indicating likely interference with responses to IL-1; the pro-inflammatory cytokines IL-1, IL-6, IL-12, TNF-a, and RANTES (CCL5), and cytokines produced by monocytes and macrophages, including granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF); other tolllike receptor proteins (in addition to Traf6), including JNK1, JNK2 and Tab1; Scya2 (small inducible cytokine A2 ¼ monocyte chemoattractant protein 1); and various intracellular adhesion molecules (ICAMs), as well as the vascular cell-adhesion molecule VCAM-1, the content of which is locally increased in atheromas. The inhibition of JNK1, together with stimulation of c-JUN (i.e. the Jun oncogene) and the previously reported superoxide-scavenging activity of mangiferin, suggests that mangiferin may protect cells against oxidative damage and mutagenesis. Taken together, these results indicate that mangiferin modulates the expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases, and raise the possibility that it may be of value for the treatment of inflammatory diseases and/or cancer (109).

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Joydeep Das et al. (27) studied D-galactosamine (GAL)induced hepatotoxicity in rats, which animals showed elevated activities of serum ALP, ALT, increased levels of triglycerides, total cholesterol, lipid-peroxidation, and reduced levels of serum total proteins, albumin, and cellular GSH. Besides, the exposure of hepatocyte cultures to GAL (5 mM) induced apoptosis and necrosis, and increased the production of ROS and NO. Signal transduction studies showed that GAL exposure significantly increased the nuclear translocation of NFkB and elevated the expression of iNOS protein (26). The same exposure also elevated TNF-a, IFN-g, IL-1b, IL-6, IL-12, and IL-18 levels and decreased the level of IL-10 mRNA Furthermore, GAL also decreased the protein expression of Nrf2, NADPH:quinine oxidoreductase-1, heme oxygenase-1, and GSTa. However, mangiferin administration to GAL-intoxicated rats or co-incubation of hepatocytes with mangiferin significantly altered all of these GAL-induced adverse effects. In conclusion, the hepatoprotective role of mangiferin was due to induction of antioxidant defense via the Nrf2 pathway and reduced inflammation via the inhibition of NFkB activity. Recent studies showed that mangiferin has potential as an antioxidant and an antitviral agent. In one study, the effect of mangiferin on rat colon carcinogenesis induced by a chemical carcinogen, azoxymethane (AOM), was evaluated. Two experiments were performed: a short-term assay to investigate the effects of mangiferin on the development of preneoplastic lesions elicited by AOM, i.e. meaning the ACF ¼ the preneoplastic lesions] aberrant crypt foci (ACF) and a subsequent long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in the diet significantly inhibited ACF development in rats treated with AOM compared with that in the rats treated with AOM alone (64.6 ± 22.0 versus 108.3 ± 43.0). In the long-term assay, the group treated with 0.1% mangiferin in the initiation phase of the experimental protocol had a significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3 and 41.8% reductions in the incidence and multiplicity, respectively, compared with those for the group treated with AOM alone). In addition, the cell proliferation in the colonic mucosa was reduced in rats treated with mangiferin (65–85% reduction compared with that for the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemopreventive agent (33). Guha et al. (32) Showed mangiferin to have in vivo growthinhibitory activity against ascitic fibrosarcoma in Swiss mice. Following in vivo or in vitro treatment, it also enhanced the cytotoxicity of the splenic cells and peritoneal macrophages of normal or tumor-bearing mice toward the tumor cells. In vitro treatment of the splenic cells of tumor-bearing mice with mangiferin resulted in augmented killing of tumor cells, both those resistant and those sensitive to natural killer cells. Mangiferin was also found to antagonize in vitro the cytopathic effect of HIV. The drug appears to act as a potent biological response modifier with antitumor and antiviral effects. Overall, a vast majority of these studies indicate that mangiferin can inhibit tumor initiation, progression, and metastasis in a wide variety of preclinical cancer models.

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Pharmacokinetics of mangiferin Although mangiferin, an active component of traditional Chinese herbal medicine, is reported to have various pharmacological effects, the limited number of pharmacokinetic studies has limited its wide application. For evaluation of the pharmacokinetics of mangiferin in humans, a sensitive highperformance liquid chromatography–mass spectrometry (HPLC–MS) method for the determination of mangiferin in rat plasma was developed (110). The proposed HPLC–MS method is selective, precise, and accurate enough to enable the identification and quantification of mangiferin for use in clinical studies. After a single oral administration of 0.1, 0.3 or 0.9 g mangiferin, the pharmacokinetics of mangiferin was successfully obtained in 21 healthy male Chinese volunteers (110). The pharmacokinetics parameters were calculated, and the pharmacokinetics of mangiferin was fitted to a noncompartmental model. The mangiferin concentration in plasma reached 38.64 ± 6.75 ng/mL about 1 h after oral administration of 0.9 g mangiferin, and the apparent elimination half-life (t1/2) was 7.85 ± 1.72 h. The absorption of mangiferin was increased with the administration of a large dose of the polyphenol, and it was concluded that the pharmacokinetics of mangiferin in human was nonlinear.

Conclusions This review has summarized the reported chemopreventive and therapeutic potential of mangiferin in various cancer models. Evidence from both in vitro and in vivo studies suggests that mangiferin can indeed suppress multiple molecular targets that play a pivotal role in both chronic inflammation and cancer. However, in the future more detailed investigations are needed to completely understand its exact mechanism of action against different cancers. Also, mangiferin has been importantly found to be bioavailable following oral administration to mice, and human pharmacokinetics and pharmacodynamics profiles have been obtained by the use of liposomal mangiferin. Various lines of evidence discussed above, show the capability of mangiferin to suppress various key steps of tumor initiation, progression, and promotion and clearly vindicate its traditional use over the past hundreds of years for the treatment of inflammatory diseases, including cancers. Additional clinical trials are required to fully exploit its reported efficacy for the prevention and treatment of various malignancies.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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