188. Prenylated Dihydrochalcones from Artocarpus altilis as Antiausterity Agents

ARTICLE IN PRESS Prenylated Dihydrochalcones from Artocarpus altilis as Antiausterity Agents Mai Thanh Thi Nguyen*,1, Nhan Trung Nguyen*, Suresh Awale† *Faculty of Chemistry, University of Science, Vietnam National University, Hochiminh City, Viet Nam † Frontier Research Core for Life Sciences, University of Toyama, Toyama, Japan Corresponding author e-mail address: nttmai@hcmus.edu.vn Contents Introduction Chemical Constituents of A altilis Biosynthesis of Prenylated Phenolic Compound Cytotoxicity of Prenylated Flavonoids and Dihydrochalcones in A altilis 4.1 Cytotoxicity of Prenylated Flavonoids 4.2 Cytotoxicity of Prenylated Dihydrochalcones 4.3 Antiausterity Activity of Prenylated Dihydrochalcones 4.4 Toxicology of A altilis Conclusions and Future Perspectives References 31 33 33 36 36 39 40 42 43 43 Abstract Human pancreatic cancer cell lines have remarkable tolerance to nutrition starvation, which enables them to survive under a tumor microenvironment A novel antiausterity strategy in anticancer drug discovery led to the discovery of agents that preferentially inhibit the survival of cancer cells under low nutrient conditions Artocarpus altilis (Family: Moraceae) is commonly referred to as breadfruit, traditionally for the treatment of many diseases Many prenylated flavonoid and prenylated chalocones together with their cancer cell cytotoxicity were reported from this plant This chapter briefly summarizes the constituents, biosynthesis, cytotoxicity, and antiausterity activity on PANC-1 human pancreatic cancer cell line of A altilis INTRODUCTION Human pancreatic cancer is the most fatal form of cancer worldwide, with a 5-year survival rate of less than 5% [1] The annual mortality rate from The Enzymes ISSN 1874-6047 http://dx.doi.org/10.1016/bs.enz.2015.05.005 # 2015 Elsevier Inc All rights reserved 31 ARTICLE IN PRESS 32 Mai Thanh Thi Nguyen et al this malignancy closely approximates the annual incidence rate [2,3] Once diagnosed, the average life expectancy is months It is the fifth leading cause of cancer-related mortality in Japan and other industrialized countries [3] Until now, no effective treatment has been available [4,5] Human pancreatic cancer shows resistance to most conventional chemotherapeutic drugs in clinical use, such as paclitaxel, doxorubicin, and cisplatin [6] At present, gemcitabine and S-1 (tegafur + gimeracil + oteracil potassium) are the only standard regimens for advanced pancreatic cancer [6–10] Therefore, effective chemotherapeutic agents against this disease are urgently needed Human pancreatic tumors are hypovascular in nature [11], causing a limited supply of nutrients and oxygen to reach the aggressively proliferating tumor cells [12] As tumor cells proliferate, the demand for essential nutrients and oxygen exceeds the supply Consequently, large areas of tumor survive under the hostile environment characterized by nutrient and oxygen starvation Yet, human pancreatic tumor cells show the extraordinary ability to tolerate such extreme states through the modulation of energy metabolism [13] While normal human cells die within 24 h under nutrient starvation, some human pancreatic cancer cell lines can survive up to 72 h in the complete absence of nutrients such as glucose, amino acids, and serum [13] This remarkable tolerance to nutrient starvation is one of the key factors for survival and progression of pancreatic tumors Therefore, agents that retard the tolerance of cancer cells to nutrient starvation represent a novel approach in anticancer drug discovery [14] In an effort to discover antiausterity strategy-based natural anticancer agents, researchers have screened thousands of medicinal plants for their preferential cytotoxicity using PANC-1 human pancreatic cancer cell line and discovered arctigenin and angelmarin as potent antiausterity strategybased anticancer agents with significant in vivo anticancer activity against PANC-1 tumor in nude mice [14,15] Based on this strategy, many reports demonstrated that there were many natural products possessed antiausterity activity from medicinal plants such as Artocarpus altilis, Boesenbergia pandurata, Uvaria dac, Caesalpinia sappan, etc [16–19] In this chapter, we focus on A altilis A altilis (Parkinson ex F.A Zorn) Forsberg (Moraceae) is a tree of moderate size and is widely cultivated in tropics as staple crop, animal feed, and construction material Its leaves have been used traditionally for the treatment of liver cirrhosis, hypertension, gout, hepatitis, and diabetes [16] Many current researches have investigated the pharmacological activities of A altilis including anti-inflammatory activity, antifungal potential, ARTICLE IN PRESS Prenylated Dihydrochalcones from A altilis 33 antibacterial activity, antidiabetic activity, nutritional assessment, as cosmetic agent, ACE inhibitors, antioxidant activity, cytotoxicity to cancer cell lines, and melanin biosynthesis inhibition [20] Here, we summarize the literature on the chemical constituents, biosynthesis, cytotoxicity, and antiausterity activities of A alitilis which support its promise for improving human health CHEMICAL CONSTITUENTS OF A ALTILIS Over 130 compounds are identified in various organs of the tree of A altilis, more than 70 of which derived from the phenylpropanoid pathway, including a number of prenylated dihydrochalcones [16–25], prenylated flavonoids [21–23,25–32], and prenylated aurones [25,33] together with some triterpenoids and phenolic compounds [34–37] (Fig 1–4) BIOSYNTHESIS OF PRENYLATED PHENOLIC COMPOUND Prenylated phenols are hybrid compounds biosynthesized from a phenolic skeleton and a prenyl—C5 or geranyl—C10 unit The phenolic skeleton derives mainly from the metabolism of shikimic acid via cinnamoyl-CoA [38] or from an acetate metabolic pathway [39] Both of these pathways would provide chalcone precursor and further cyclization to afford flavonoid skeletons The prenyl or geranyl units come from isoprenoid mevalonate (HMG-CoA reductase) [40] or deoxyxylulose phosphate (non-mevalonate) pathways [41] The enzymatic prenyltransferase system uses an active diphosphate form—dimethylallyl pyrophosphate, or geranyl pyrophosphate to connect it with the phenolic skeletons [42] It is assumed that the plant prenyltransferase is located in the envelope membrane of plastids and that both reactants must be bound to the active site of the enzyme before the reactions can be happened The binding order has not yet been elucidated, but the aromatic intermediate can probably not be bound without the binding of the diphosphate form of the isoprenoid A presumable mechanism of reaction has been postulated: isoprene-PP binds to the transferase active site and is correctly oriented through diphosphatecation (Mg2+ and/or basic side chains) interactions; the aromatic acceptor then binds, starts to form a geranyl carbocation through pyrophosphate loss This carbocation then performs an electrophilic attack on the aromatic acceptor that is terminated by the neutralization of the acceptor through loss ARTICLE IN PRESS 34 Figure The prenylated flavonoids of A altilis Mai Thanh Thi Nguyen et al ARTICLE IN PRESS Figure The prenylated dihydrochalcones of A altilis ARTICLE IN PRESS 36 Mai Thanh Thi Nguyen et al Figure The prenylated aurones of A altilis of a proton The site of the bond is the O or C atom, depending on the nature of prenyltransferase and the substrate [43] (Fig 5) CYTOTOXICITY OF PRENYLATED FLAVONOIDS AND DIHYDROCHALCONES IN A ALTILIS 4.1 Cytotoxicity of Prenylated Flavonoids Some compound illustrated in Fig displayed antitumor activity through diverse mechanisms Table below provides a number of prenylated flavonoids and specific tumor cell lines against which they show direct cytotoxicity In most cases, cytotoxicity was monitored using the Cell Viability Assays, i.e., Tetrazolium Reduction Assays (MTT, MTS, XTT, and WST-1) Treatment of cells with these compounds can cause a decrease in cell viability, and then the cells undergo rapid necrosis or activate a programmed death (apoptosis) In this table, these compounds exhibited cytotoxicity against a number of cell lines from a wide range of tumors, including oral cancer, breast cancer, lung cancer, hepatoma, colorectal cancer, prostate cancer, stomach cancer, kidney cancer, ovarian cancer, leukemia, and melanoma In the table, some prenylated flavonoids showed their cytotoxicity with many tumor cell lines Compounds (31) and (32) were named morusin and artonin E, respectively In this case, each of these compounds exhibit cytotoxicity against almost all tumor cell lines Morusin (31) showed intermediate cytotoxicity (10 μM < IC50 values < 80 μM) against liver cancer (SMMC-7721) and gastric cancer (SGC-7901 and BGC-823) [49] On the other hand, the evaluation of the efficacy as a 5-LOX inhibitor or an antitumor agent of morusin was carried out, i.e., the binding affinity of ARTICLE IN PRESS Prenylated Dihydrochalcones from A altilis Figure Some phenolic, triterpenoids, and aliphatic compounds of A altilis 37 ARTICLE IN PRESS 38 Mai Thanh Thi Nguyen et al Figure The biosynthesis pathway of prenylated phenolic compounds protein–ligand complexes were examined by automated docking method [46] To confirm this result, the effect of morusin on tumor cell proliferation/viability was examined; it inhibited MDA-MB-231 and MCF-7 cell (breast tumor) strongly with an IC50 of 3.2 and 3.4 μM, respectively, and inhibited A-549 cells (lung cancer) with an IC50 of 3.1 μM [46] Artonin E (32) was expected to be an antitumor promotor in a two-stage carcinogenesis experiment by considering the similarity of the structures with morusin (31) The tumor-promotion mechanism suggested that tumornecrosis factor-α (TNF-α acts as a tumor promotor in BALB/3T3 cell transformation) induced by okadaic acid acts as a mediator of human carcinogenesis [50] So the inhibitory examinations of some prenylated flavonoids (31, 32) on TNF-α release stimulated by okadaic acid using BALB/3T3 cells were carried out; and artonin E (32) was the most potent inhibitor on the both tests (inhibitory effect on 5-LOX and TNF-α) than morusin (31) [50] Artonin E (32) also exhibited potent cytotoxicity against many tumor cell lines, e.g., Colon-38, HCT-8, MDA-MB-231, PC-3, L-1210, SK-MEL-2; especially this compound showed strong cytotoxicity ARTICLE IN PRESS Prenylated Dihydrochalcones from A altilis 39 Table Some Prenylated Flavonoids and Their Cytotoxicity Target Cancer Compounds Cell Lines Cancer Type References 4, 12, 20, 21, 23, 27, 30–32, 36–38 KB Oral cancer [27,44,45] 4, 12, 23, 30–32, 36–38 BC Breast cancer [27,45] 3, 12, 21, 24, 31, 32 MCF-7 [46–48] 12, 31, 32 MDA-MB231 [46,47] 12, 24, 31 A-549 37 NCI-H187 20, 21, 27 PLC/PRF/5 31 SMMC-7721 BGC-823 Lung cancer [46,47] [45] Liver cancer [44] [49] Gastric cancer [49] SGC-7901 32 Colon-38 12, 32 HCT-8 Colon cancer [50] [47] 1A9 Prostate cancer [47] 32 PC-3 Ovarian cancer [47] 3, 21 TK-10 Renal cancer [48] UACC-62 Melanoma [48] 32 SK-MEL-2 L-1210 29, 35, 36, 37 [47] Leukemia P-388 [50] [51–53] against 1A9 (ED50 < 1.25 μg/mL) and significant activity against MCF-7 (ED50 ¼ 2.2 μg/mL) [47] 4.2 Cytotoxicity of Prenylated Dihydrochalcones Some prenylated dihydrochalcone (Fig 2) showed their cytotoxicity with some tumor cell lines Compounds (41), (45), and (51) exhibited moderate cytotoxicity against three human cancer cell lines (SPC-A-1, SMMC7721, and SW-480) Compound (51) was the most potent against the ARTICLE IN PRESS 40 Mai Thanh Thi Nguyen et al Table Some Prenylated Dihydrochalcones and Their Cytotoxicity Compounds Target Cancer Cell Lines Cancer Type References 41, 45, 51 [21] 50 SPC-A-1 Lung cancer SMMC-7721 Liver cancer SW-480 Colon cancer P-388 Leukemia [54] DU145 Prostate cancer [55] SPC-A-1 and SW-480 cells, and relatively more active than positive control (9-fluorouracil) [21] (Table 2) Recently, Jeon et al applied the bioassay-guided isolation to identify the active components from A altilis extract This study showed that the isolated compound (50) is a STAT (signal transducers and activators of transcription) inhibitor [55] Also compound (50) suppressed STAT3 activity in DU145 prostate cancer cell line in a dose- (IC50 value of 20 μM) and timedependent manner (100% inhibition occurring h after treatment with 50 μM) [55] Further, this compound downregulated the expression of STAT3 target genes and selectively inhibited the growth of DU145 activated-STAT3 prostate cancer cell line [55] 4.3 Antiausterity Activity of Prenylated Dihydrochalcones Pancreatic tumors are hypovascular and supply only a limited amount of essential nutrients and oxygen to aggressively proliferating cells Consequently, these cells live in a hostile microenvironment under chronic metabolic stress conditions Pancreatic cancer cells show resistance to almost all known chemotherapeutic agents such as 5-Fu, paclitaxel, doxorubicin, cisplatin, and campothecin, and exhibits only minimal activity as a single agent in pancreatic cancer [6] Gemcitabine currently represents the standard chemotherapeutic drug for metastatic and advanced pancreatic cancer, but it only leads to a modest improvement in survival [15] Therefore, the development of novel agents is urgently needed The hypovascular tumors, and poorly differentiated cancer cells such as PANC-1, AsPC-1, BxPC-1, and KP-3 show an inherent ability to tolerate extreme conditions (low nutrient and oxygen supply) by modulating their energy metabolism [4] Thus, tolerance to nutrient starvation (austerity) might be a part of the biological response to insufficient blood supply, and the resistance of the cells to nutrient deprivation may serve as a novel ARTICLE IN PRESS Prenylated Dihydrochalcones from A altilis 41 biochemical approach to cancer treatment Considering this hypothesis, a novel screening strategy (termed as “antiausterity strategy”) was proposed for the discovery of anticancer agents that preferentially eliminates the tumor cells capability to survive under low-nutrition condition [14] In 2014, based on the cytotoxicity activity reported from A altilis, Nguyen et al studied cytotoxic activity of the methanolic extract of the leaves and isolated geranyl dihydrochalcones against a PANC-1 human pancreatic cancer cell line in normal nutrient-rich medium (DMEM) and nutrient-deprived medium (NDM), utilizing an antiausterity strategy The results demonstrated that the methanolic extract displayed preferential cytotoxicity against PANC-1 cells in NDM condition at 50 μg/mL, while compounds 40, 42, 43, 45, 49, 50, 53 (Fig 2) showed preferential cytotoxicity in NDM without apparent toxicity in DMEM condition Their PC50 values, which means the 50% preferential cell death in NDM without cytotoxicity in DMEM are listed in Table Arctigenin, an antiausterity strategybased anticancer agent which was used as a positive control in this study, showed a PC50 value of 0.83 μM Paclitaxel, a well-known anticancer agent, was virtually inactive Among them, 43 and 49 displayed the most potent preferential cytotoxic activity with PC50 values of 8.0 and 11.1 μM, respectively Sakenin F (43) was further evaluated for its effect on the cell morphology of PANC-1 cells in NDM The microscopic images were analyzed under phase-contrast and fluorescence mode using ethidium bromide/acridine orange (EB/AO) reagent AO is a cell-permeable dye and gives a green (light gray in the print version) or orange (light gray in the print version) fluorescence in live cells EB is permeable to dead cells only and gives a Table Preferential Cytotoxicity of Prenylated Dihydrochalcones Against PANC-1 Human Pancreatic Cancer Cell Line in Nutrient-Deprived Medium (NDM) Compounds PC50 (μM) References 40 41.2 42 19.9 43 8.0 45 18.8 49 11.1 50 75.2 53 58.7 [16] ARTICLE IN PRESS 42 Mai Thanh Thi Nguyen et al Figure Morphology of PANC-1 cells in NDM: (A) control, (B) treated with μM of 43, (C) treated with 10 μM of 43, (D) treated with 10 μM of 43, phase contrast red (dark gray in the print version) fluorescence As shown in Fig 6A, the cells in control were alive and stained with AO giving a green (light gray in the print version) fluorescence However, when treated with 43, the morphology of PANC-1 cells was distinctly altered (Fig 6B–D) with an increasing population of dead cells (red; dark gray in the print version) The phase-contrast image of PANC-1 cells treated with 43 showed rounding of the cell membrane, rupture, and disintegration of cellular contents to the medium (Fig 6D) 4.4 Toxicology of A altilis Sairam and Urooj demonstrated that there was no acute toxicity of A altilis leaf and bark extracts using adult Wistar strain albino rats [56] In this acute toxicity study, no mortality or any toxic reaction was recorded in any group after 14 days of administering the extracts (2000 mg KgÀ1 BW) The extracts (ALA, ABA, ALM, and ABM) did not cause any behavioral or physical changes in experimental rats There was no significant difference in the biochemical parameters analyzed between the groups Slight elevation in ARTICLE IN PRESS Prenylated Dihydrochalcones from A altilis 43 activities of AST and ALT in extract treated groups was observed, but this did not exert any deleterious effect on the normal metabolism which was supported by the histopathology of liver Histopathological studies showed no remarkable changes after 14 days of oral administration of ALA, ABA, ALM, and ABM extracts The study contributes to establishing the nontoxic quality parameters of A altilis leaf and bark parts and the results suggest the safety of the extracts in therapeutic uses [56] CONCLUSIONS AND FUTURE PERSPECTIVES Natural products, either extracted or as pure compounds, contain diverse chemicals that provide unlimited prospects for the development of new drugs It has been reported that A altilis contain numerous beneficial biologically active 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