Chemistry and Anticarcinogenic Mechanisms of Glycoalkaloids

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Chemistry and Anticarcinogenic Mechanisms of Glycoalkaloids Produced by Eggplants, Potatoes, and Tomatoes Mendel Friedman* Western Regional Research Center, Agricultural Research Service, United States Department Agriculture, Albany, California 94710, United States ABSTRACT: Inhibition of cancer can occur via apoptosis, a genetically directed process of cell self-destruction that involves numerous biomarkers and signaling pathways. Glycoalkaloids are nitrogen-containing secondary plant metabolites found in numerous Solanaceous plants including eggplants, potatoes, and tomatoes. Exposure of cancer cells to glycoalkaloids produced by eggplants (α-solamargine and α-solasonine), potatoes (α-chaconine and α-solanine), and tomatoes (α-tomatine) or their hydrolysis products (mono-, di-, and trisaccharide derivatives and the aglycones solasodine, solanidine, and tomatidine) inhibits the growth of the cells in culture (in vitro) as well as tumor growth in vivo. This overview comprehensively surveys and consolidates worldwide efforts to define the following aspects of these natural compounds: (a) their prevalence in the three foods; (b) their chemistry and structure−activity relationships; (c) the reported factors (biomarkers, signaling pathways) associated with apoptosis of bone, breast, cervical, colon, gastric, glioblastoma, leukemia, liver, lung, lymphoma, melanoma, pancreas, prostate, and squamous cell carcinoma cell lines in vitro and the in vivo inhibition of tumor formation and growth in fish and mice and in human skin cancers; and (d) future research needs. The described results may make it possible to better relate the structures of the active compounds to their health-promoting function, individually, in combination, and in food, and allow the consumer to select glycoalkaloid-containing food with the optimal content of nontoxic beneficial compounds. The described findings are expected to be a valuable record and resource for further investigation of the health benefits of food-related natural compounds. KEYWORDS: glycoalkaloids, α-solamargine, α-solasonine, solasodine, α-chaconine, α-solanine, solanidine, α-tomatine, tomatidine, eggplants, potatoes, tomatoes, chemistry, analysis, cancer cell inhibition, tumor inhibition, mechanisms, biomarkers, signaling pathways, immunostimulating effects, membrane disruptive effects, tomatine-cholesterol affinity, additive effects, synergistic effects, human health, research needs

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INTRODUCTION Carcinogenesis is a sequential multistage cellular process consisting of tumor initiation, tumor promotion, and tumor progression. Because tumor promotion may be the only reversible event during cancer development, its suppression may be regarded as an effective way to inhibition carcinogenesis. Because glycoalkaloids, in addition to inhibiting cancer cells, may also inhibit normal cells, a key consideration for their use in cancer prevention and treatment should be the ratio of effective preventive or therapeutic to toxic dose. Moreover, whether glycoalkaloids from different food sources can additively or synergistically enhance anticarcinogenic effects of anticancer drugs is also an active area of research. The Solanaceae plant family includes eggplant, potato, and tomato. Eggplant and tomato fruit and potato tubers and their processed products serve as major, inexpensive low-fat food sources, providing energy, protein, fiber, vitamins, and bioactive compounds including glycoalkaloids. Glycoalkaloids are secondary plant metabolites that may be involved in the defense of the plants against phytopathogens, including bacteria, fungi, and viruses. Glycoalkaloids are produced in the edible parts of the plants as well as in leaves, flowers, roots, and, in the case of potatoes, also in sprouts. They generally occur in the plant as steroidal glycosides. Eggplants produce the trisaccharides αsolamargine and α-solasonine, potatoes, the trisaccharides αchaconine and α-solanine, and tomatoes, the tetrasaccharides α© XXXX American Chemical Society

tomatine and dehydrotomatine. Uncultivated (wild) potato varieties produce additional glycoalkaloids (Figure 1). The reason why nature created two glycoalkaloids and not one in the three cultivated plants may be because the evolutionary approach makes it possible for the two glycoalkaloids to exert the observed synergistic effects described below, thus allowing the plant to have a smaller total amount of the two glycoalkaloids while maintaining resistance against phytopathogens. Previously, we evaluated about 18 eggplant, potato, and tomato glycoalkaloids and some of their hydrolysis products (metabolites) for their ability to inhibit the growth (antiproliferative activities) of several human cancer cell lines.1,2 All of the test compounds inhibited growth of the tumor cells but at different rates. These studies seemed to have stimulated interest in the chemopreventive mechanisms of the anticarcinogenic activities in vitro in cancer cells and in vivo in tumors. Because humans may consume at least six glycoalkaloids in their diet from the mentioned three widely consumed foods, there is a need to further define the possible beneficial effects of glycoalkaloids consumed individually, in Received: February 11, 2015 Revised: March 17, 2015 Accepted: March 22, 2015

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DOI: 10.1021/acs.jafc.5b00818 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

Figure 1. Structures of the aglycones and glycoalkaloids found in Solanum.137,140,141

nervous system depressing, hypolipodemic, and hypotensive properties of eggplants, reviewed by Das and Barua and Sun et al.8,9 We do not know whether eggplants also possess anticarcinogenic properties. The fruits of the eggplant are one of the most widely consumed vegetables in the world, with the most popular species being Southeast Asia-domesticated S. melongena L.10 These authors used liquid chromatography−mass spectrometry methods to compare the contents of the major eggplant glycoalkaloids (solamargine and solasonine) of S. melongena to the allied accession of the Africa-cultivated S. aethiopicum and S. macrocarpon. The results show that (a) fruits of S. aethiopicum and S. melongena contained (in mg/100 g fresh weight) 0.58− 4.56 α-solamargine and 0.17−1.0 α-solasonine and (b) the corresponding much higher values for S. macrocarpon are 124− 197 and 16−23, respectively, suggesting that this accession might not be safe for consumption. A related study of 10 eggplant lines and three allied species (S. aethiopicum, S. integrifolium, and S. sodomaeum) confirmed that the allied species had higher glycoalkaloid content than the widely consumed eggplants and that the glycoalkaloid content

combination, and as part of the diet against cancer cells and tumors. To help stimulate needed studies further, the main objective of this review is to unify the scattered information on the anticarcinogenic potential of the food-related glycoalkaloids. It should be noted that glycoalkaloids are reported to exhibit other beneficial as well as adverse effects in animals and humans. These aspects are beyond the scope of this review. They are comprehensively covered in our previous publications.3−7

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CHEMISTRY AND PREVALENCE OF GLYCOALKALOIDS IN FOOD Eggplants. Solanum melongena Linn. is an herbaceous plant with coarsely lobed leaves, white to purple flowers, and widely consumed fruit that can be eaten raw, cooked, or pickled.8 The following selected studies show that eggplants contain several classes of bioactive compounds, including anthocyanidins, flavonoids, saponins, and glycoalkaloids. Individual or combinations of the bioactive compounds are probably responsible for the reported analgesic, antianaphylactic, anti-inflammatory, antioxidant, antipyretic, intraocular pressure reducing, central B


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Journal of Agricultural and Food Chemistry generally increased during fruit development and ripening.11 Bajaj et al.12 used colorimetry to determine an average glycoalkaloid content of 21 eggplant varieties, whose concentrations (in mg/100 g fresh weightt) ranged from 6.25 to 20.5 or 3.3-fold variation from the lowest to the highest value. These authors also found that the crude protein content ranged from 0.77 to 3.63 (4.7-fold variation) and that highglycoalkaloid eggplants tasted bitter. A British study used colorimetry to determine the average glycoalkaloid content of two eggplant samples of about 8 mg/100 g fresh weight.13 Kintia and Shvets14 isolated and characterized three steroidal saponins from seeds of Moldavian S. melongena. These compounds probably contribute to the observed bioactivities of eggplants. An Egyptian study15 used colorimetry and thinlayer chromatography (TLC) to identify three glycoalkaloids (solamargine, solasonine, and solanine) in S. melongena fruit, whose concentrations varied with the harvesting season. These authors also found that fruit infected with Botrytis cinerea fungi contained the solanine hydrolysis product β-solanine. French scientists used colorimetry and TLC to determine the total glycoalkaloid and furastanol saponin content of six eggplant varieties, the concentrations of which (in mg/100 g fresh weight) ranged from 1.0 to 7.2 and 3.0 to 11.2, respectively.16,17 Eanes et al.18 developed an HPLC method for the separation and determination of the following eggplant glycoalkaloids: solamargine, solasonine, chaconine, and solanine and their aglycones, solasodine and solanidine. Extracts of S. melongena and S. linnaeanum were used to determine the method of recovery, limit of detection, and limit of quantification. In agreement with our studies with potato19 and tomato20 glycoalkaloids, grilling or boiling of eggplants did not result in significant changes in the total glycoalkaloid (solamargine plus solasonine) content.21 Potatoes. Nikolic et al.22 describe a liquid−liquid system for the acid hydrolysis of potato glycoalkaloids from potato sprouts that yields 1.46 g of solanidine per 100 g of dried sprouts. Attoumbre et al.23 describe a centrifugal partition chromatography procedure for the isolation of solanidine from glycoalkaloid hydrolysates of potato skins and sprout extracts. Kuo et al.24 found that adding auxin phytohormones to cell culture tissues of the Solanum lyratum plant induced increases in the production of solanidine and solasodine levels, suggesting the availability of a new method for the production of steroidal alkaloids. Friedman and Levin7 reviewed analytical methods for investigating potato glycoalkaloids and bioactive calystegine alkaloids. Figure 2 shows the glycoalkaloid content of fresh and processed potatoes. Tomatoes. The glycoalkaloid known as tomatine consists of a mixture of two glycoalkaloids: α-tomatine and dehydrotomatine (Figure 1). In the present study, we will use the term tomatine for the 10:1 mixture. Both compounds are present in tomato fruit and leaves. Immature green tomatoes contain up to 500 mg of tomatine per kilogram of dry weight. The tomatine content of cherry tomatoes (grape tomatoes, minitomatoes) is several fold greater than that of larger size standard varieties. Because tomatine is largely degraded as the tomato ripens, the levels in red tomatoes are much lower, up to about 5 mg/kg. Consumers of high-tomatine green tomatoes and pickled green tomatoes consume high amounts of tomatine. A red tomato variant indigenous to the Andes mountains of Peru has a very high tomatine content, 500−5000 mg/kg dry wt.25 These tomatoes are consumed without

Figure 2. Makeup of total glycoalkaloids in a small sampling of a variety of potatoes and potato products. Due to the large standard deviations, ANOVA showed no statistical differences. Adapted from ref 6. Copyright 2006 American Chemical Society.

apparent acute toxic effects. Figure 3 lists the α-tomatine content of a small sampling of fresh and processed tomatoes.

Figure 3. α-Tomatine content per serving of a variety of fresh and processed tomato (or tomatillo) products. Bars sharing the same symbol are not significantly different; p < 0.05. Adapted from ref 20. Copyright 1995 American Chemical Society.

The use of gene manipulation to introduce desirable traits into tomatoes, such as tolerance to stress and pesticides and resistance to phytopathogens, raises questions about the tomatine content of the transgenic tomatoes. Our results,5 and those by other investigators,26,27 indicate that tomatine levels of transgenic tomatoes were not significantly different from those observed in the standard varieties grown under the same field conditions. By contrast, a long-term (10 year) study revealed that organically grown tomatoes had higher average tomatine content than their standard counterparts, suggesting that soil composition and environmental conditions seem to affect the tomatine content in tomato.28 The tomatine levels of tomatoes in both cropping systems ranged from 4.29 to 111.85 μg/g dry wt or a 26-fold variation from the highest to the lowest value. A related study found that the tomatidine content of 11 analyzed samples was higher in conventional tomatoes than that in organic tomatoes.29 These results suggest the possibility of future anticancer and anticholesterol studies with selected high-tomatine and high-tomatidine red tomatoes. We carried out studies designed to optimize the acid hydrolysis of the tetrasaccharide chain of tomatine to products C


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Journal of Agricultural and Food Chemistry with three, two, one, and zero sugar groups.30 A 20 min hydrolysis of tomatine in 1 N HCl at 100 °C was used for the formation of the trisaccharide β1-tomatine, the disaccharide γtomatine, and the monosaccharide δ-tomatine. Efforts to isolate the other theoretical possible trisaccharide, β2-tomatine, were unsuccessful, apparently because its xylose sugar is degraded during hydrolysis. A 70 min hydrolysis time achieved complete removal of the tetrasaccharide side chain to produce the aglycone tomatidine. Because tomatine was stable to acid hydrolysis at 37 °C, it may be stable in the acidic pH environment of the human gut. The hydrolysis products are formed by sequentially cleaving the sugars from lycotetraose (Figure 1). With this background on the structures and composition of glycoalkaloids from eggplants, potatoes, and tomatoes and some of their hydrolysis products (metabolites), we will now briefly describe reported studies designed to determine the anticarcinogenic properties and mechanisms of action of the eggplant glycoalkaloids α-solamargine and α-solasonine, their common aglycone solasodine, the potato glycoalkaloids αchaconine and α-solanine and hydrolysis products including the aglycone solanidine, and the tomato glycoalkaloids α-tomatine and hydrolysis products including aglycone tomatidine against cancer cells in culture (in vitro) and some animal and human tumors in vivo.

apoptosis of human hepatoma Hep3B cells by changing the dihedral angle of the glycosidic bond, suggesting that the carbohydrate side chains of glycoalkaloids seem to govern the affinity to steroid human necrosis factor receptors and gene expression associated with carcinogenesis. A related study suggests that cells in the G(2)/M phases are highly susceptible to solamargine-mediated apoptosis and that parallel upregulation of tumor necrosis factor receptors TNFR-I or TNFR-II on the Hep3B cells may be an independent mechanism of solamargine-mediated apoptosis.38 Blankemeyer et al.39 used a cell assay to measure the changes in membrane potentials of frog embryos induced by solamargine and solasonine. Experiments with solasonine at pH 6 and 8 suggest that the unprotonated form of solasonine is involved in the membrane potential effect and that the relative potencies of the two glycoalkaloids are similar for the observed frog embryo effects. Solamargine and solasodine inhibit cell-mediated immune functions [(antibody-dependent cellular cytotoxicity (ADCC) and natural killer cell (NK)] activity of human peripheral mononuclear cells, possibly suggesting that enhancement of the immune system could contribute to apoptosis.40 In vivo studies support this suggestion.41 These authors found that groups of mice administered solasodine rhamnosyl glycosides one-half an hour after Sarcoma 180 inoculation caused total remission of the cancer, whereas mice treated with sarcoma but without the glycosides all died within 20 days. Moreover, 10 of 12 of cured mice were resistant to the reintroduction of terminal doses of cancer. Because, in addition to apoptosis, the glycosides stimulated lasting immunity against cancer similar to that observed with a vaccine containing Corynbacterium parvum, it seems that the stimulation of immunity contributed to the observed in vivo anticancer effects. It seems that solasodine glycosides could contribute to the management of diseases such as malignancy and also be used as a prevention therapy. Below, we mention the role of immunity in the bioactivity of glycoalkaloids. Gastric Cancer Cells. Ding et al.33 isolated six glycoalkaloids from Solanum nigrum. The following four induced cytotoxicity and apoptosis in the gastric cancer cell line MGC803: solasonine, β1-solasonine, solamargine, and solanigroside P. The number and location of the α-L-rhamnose moiety and the type of sugar in the side chain as well as the presence of an OH group on the steroidal alkaloid backbone influenced relative potency. The suggested mechanism of apoptosis seems to be related to the recognized anticarcinogenic events: activation of caspase-3, cell cycle arrest, upregulation of the ratio of antiapoptotic Bax to Bcl-2 proteins, and downregulation of the mutant p53 gene. Leukemia Cells. In an effort to define how solamargine mediates cytotoxicity via oncosis in human K562 leukemia and squamous cell carcinoma KB cells, Sun et al.42 used the MTT assay to measure cytotoxicity and the release of lactate dehydrogenase (LDH) and the uptake of propidium iodide (PI) to determine leakage of cytoplasm content. Cytotoxicity and membrane disruption were triggered rapidly within minutes at the same rate by 10 μM solamargine, suggesting that apoptosis seems to be initiated by plasma membrane perturbation. These authors34 also reported that exposure of the leukemia cells to 10 μM solamargine for 30 min induced a 7-fold increase in intracellular calcium concentration, downexpression of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9 activities. These results and the observed decrease in

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ANTICARCINOGENIC PROPERTIES OF EGGPLANT GLYCOALKALOIDS Here, we briefly review mechanistic aspects associated with eggplant glycoalkaloids produced in some eggplant varieties. In addition to eggplants, numerous herbal and medicinal plants synthesize solamargine and solasonine. In fact, most of the anticancer studies mentioned below were done with glycoalkaloids isolated from these sources and not from eggplants. Because the glycoalkaloids from different plant sources are identical, we will also mention selected anticancer studies in cells, rodents, and human using glycoalkaloids from herbal and medicinal plants grown in different parts of the world. These include S. incanum,31 S. lycocarpum,32 and S. nigrum.33 Structural and Immune Effects in Apoptosis. Apoptosis is a genetically controlled (encoded), regulated, and conserved form of cell death, where the cell first undergoes nuclear and cytoplasm condensation with blebbing of the plasma membrane, DNA fragmentation, and breakdown of membrane-enclosed fragments known as apoptotic bodies, which are then engulfed rapidly by neighboring cells or macrophages.34 The cell activity thus participates in its own destruction. In many cells, but apparently not with tomatine (see below), activation of caspases by eggplant glycoalkaloids may be the ultimate effector mechanism in apoptotic pathways. TNF exhibits antiproliferative effects against various cancer cell lines in vitro and in vivo.34,35 The trisaccharide solamargine and the corresponding monoand diglycosides preferentially inhibited the uptake of tritiated thymidine by cancer cells relative to that by normal lymphocyte cells.36 These results and the observed morphological changes in the cells indicate that the action against the cancer cells involves cell lysis. On the basis of a structure−activity and molecular modeling study, Chang et al.37 concluded that the 2′rhamnose moiety of solamargine [(22S,25R)-spiro-5-ene-3β-ylα-L-rhamnopyranosyl-(1→2glu)-O-α-L-rhamnopyranosyl(1→ 4glu-β-D-glucopyranose)-solasodine] acts by penetrating the cell membrane by diffusion and then triggers death by D


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mechanism by which solamargine activates the p53 gene remains unclear. Multiple Cancer Cell Lines. The Chinese medicinal herbs Solanum incanum and Solanum nigrum Linn. contain the steroidal glycoalkaloids solamargine, solanine, and solasonine. An ethanol extract of S. nigrum was found to inhibit the growth of MCF-7 breast cancer and to induce apoptosis of tumor cells.50 Solanine isolated from this plant was found to inhibit tumors in the following cell lines (IC50 values in μg/mL): Hep G2 human carcinoma (14.5), SGC-7901 human gastric carcinoma (>50), and LS-174 human large intestine cancer cells (>50). The inhibitory action of solanine was accompanied by a decrease in the content of Bcl-2 protein in the Hep G2 cells. These data show that Hep G2 cells showed the greatest sensitivity to inhibition by solanine. Munari et al.32 evaluated the antiproliferative effects of solamargine and solasonine against the following tumor cell lines: murine melanoma (B16F10) and human colon carcinoma (HT29), breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa), hepatocellular liver carcinoma (Hep G2), and glioblastoma (MO59J, U343, and U251). Solamargine showed the most pronounced activity, with IC50 values ranging from 4.58 to 18.23 μg/mL. The lowest IC50 values (highest activities) were observed against Hep G2, with an IC50 value for solamargine of 4.58 and for solasonine of 6.01. These results show that the test substances behaved as broad-spectrum anticarcinogens. Three solasodine glycoside derivatives prepared by transglycosylation exhibited strong cytotoxicity against four cancer cell lines, suggesting that they might serve as lead candidates for cancer chemotherapy.51 Multiple Drug Resistance. Multidrug resistance (MDR) is one of the major causes of the failure of conventional treatments of cancer. MDR is often associated with the expression of P-glycoprotein (P-gp), which acts as a drug efflux pump to transport intracellular drugs out of cells, thus imparting drug resistance to tumor cells.52 These authors found that solamargine has broad-spectrum cytotoxic activity against multiple MDR cell lines (human myelogenous leukemia K562 cell line and its multidrug resistant counterpart K562/ AO2) and that the P-gp−actin association pathway might be involved in the apoptosis, suggesting that the glycoalkaloid bypasses the MDR mechanism. Enhancement of Cancer Drug Potencies. Solamargine synergistically enhanced the effects of cancer drugs including methotrexate, 5-florouracil, cisplatin,46,47 and epirubicin45,53 in several cancer cell lines, suggesting that it may have potential use in combination therapy for breast and lung cancers. Mouse Cancers. A mixture of solasodine glycosides was effective in vivo against murine Sarcoma 180 (S180).54 Mice in terminal stages of cancer became symptom free by a single dose. Because rhamnose inhibited the therapeutic effect, the authors suggest that the binding of glycosides to tumor cells may be mediated through the rhamnose carbohydrate of the trisaccharide side chain of solamargine. Human Cancers. A 0.005% solasodine glycoside cream applied topically was effective in causing regression of human basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) without adverse effect on the liver, kidneys, or blood system.55 A solamargine-rich extract from S. incanum induced apoptosis in human SCC cells cells by upregulating the expression of TNFRs and Fas and downstream adaptors of TNF-α and Fas signaling pathways, triggering the mitochon-

membrane potential and release of cytochrome c suggest that an induced lysosomal−mitochondrial death pathway is involved in the cytotoxicity. Because the cells do not show an early increase in reactive oxygen species (ROS) production before apoptosis, the lysosomal rupture does not seem to be associated with oxidative stress. Liver Cancer Cells. Solamargine isolated from Solanum nigrum inhibited the growth and induced apoptosis of human hepatoma Hep G2 and SMMC-7721 cells lines via cell cycle arrest at G2/M phase and upregulation of caspase-3 expression, the so-called executioner caspase and mediator of DNA fragmentation and nuclear condensation, suggesting that the glycoalkaloid could be used to treat liver cancer.43 Lung Cancer Cells. Solamargine exhibited superior cytotoxicity in four human lung cancer cell lines, with IC50 values ranging from 3 to 7.2 μM, and increased binding of TNF-α and TNF-β to the lung cancer cells.35 The glycoalkaloid induced release of cytochrome c, downregulation of antiapoptotic Bcl-2 and Bcl-xL proteins, increase in caspase-3 activity, and DNA fragmentation.35 These observations and the additional finding that TNF-resistant lung cancer cells became susceptible after exposure to solamargine suggest that the compound should be studied for its therapeutic value against human lung cancers. Other investigators reported that the anticarcinogenic activity of solamargine is associated with the downregulation of HER-2 and upregulation of Fas and tumor necrosis factor receptor (TFNR) expression, which triggers the mitochondrial-mediated cell apoptosis pathway and sensitizes human lung cancer cell and A540 adenocarcinoma cells to chemotherapy, and that it potentiated the death of lung cancer H661 cells induced by the drugs herceptin and epirubicin44,45 as well as the death of lung and breast cancer cells induced by the drug cisplatin.46,47 A detailed mechanistic study48 revealed that solamargine inhibited growth and induced apoptosis of non-small-cell lung cancer cells in a time- and dose-dependent manner and increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in a time-dependent manner. It also inhibited phosphorylation and protein expression of signal transducer and activator of transcription 3 (Stat3), which was abrogated by SB203580, a specific inhibitor of p38 MAPK, and induced protein expression of the p21 cyclin-dependent kinase inhibitors. Although silencing of Stat3 had no further effect, exogenous expression of Stat3 overcame the effect on cell proliferation. These results show that solamargine inhibits proliferation and induces apoptosis in lung cancer cells through p38 MAPK-mediated suppression of phosphorylation and protein expression of Stat3, followed by induction of Stat3’s downstream effector, p21. Osteosarcoma Cells. An investigation by Li et al.49 on the role of the p53 gene in the proapoptotic action of solamargine in human U2OS cells using the microculture tetrazolium (MTT) and several other bioassays found that solamargineinduced apoptosis was associated with chromatin condensation, formation of apoptotic bodies, exposure of phosphatidylserine on the extracellular surface, increase in mRNA and protein levels of p53 and Bax (a proapoptotic protein), reduction in the expression of Bcl-2 (an antiapoptotic protein), loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3 and -9 enzymes. These results suggest that solamargine activates the mitochondria-mediated apoptotic pathway via both p53 transcription-dependent and -independent mechanisms. The authors conclude that the E


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concentration-dependent in the range of 0.1−10 μg/mL (0.117−11.7 nmol/mL), (b) α-chaconine was more active than α-solanine, (c) some mixtures exhibited synergistic effects, whereas others produced additive ones, (d) the different cancer cells varied in their susceptibilities to destruction, and (e) the destruction of normal liver cells was generally lower than that of liver cancer cells. The decreases in cell populations were also observed visually by phase contrast microscopy (Figure 4). This

drial apoptotic pathway, upregulating cytochrome c and Bax, and downregulating Bcl-X(L).31 A once-daily application of a topical solamargine gel to the skin caused the disappearance of UVB-induced microinvasive SCCs in 27 of 30 hairless mice within 10 weeks. In addition, the gel cured 10 of 13 patients with actinic keratosis (AK) after 16 weeks. The authors suggest that the extract may be an ideal candidate for the treat of AK with minimal side effects on normal skin. Goldberg et al.56 effectively treated cancer of the human penis, called Bowen’s disease (in situ squamous cell carcinoma of the skin), with low concentrations of a mixture of solasodine glycosides and liquid nitrogen. Punjabi et al.57 evaluated, in a double-blind randomized study, the safety and efficacy of a cream containing a 0.005% mixture of solasodine glycosides (Zycure) for the treatment of basal cell carcinoma in humans (males, n = 50; females, n = 44) at 10 centers in the United Kingdom. The primary efficacy end point was histologically confirmed clearance of the basal cell carcinoma at the end of 8 week treatment. The results show that the treatment is a safe therapy for basal cell carcinoma, with a cure rate of 66% at 8 weeks and 78% at a 1 year followup. In a related in vivo study, Tiossi et al.58 used an extract of Solanum lycocarpum fruit containing 45% each of solamargine and solasonine to prepare a topical formulation and to optimize its penetration in vitro to porcine skin and in vivo to the skin of hairless mice. The results showed that pH 6.5 was optimal for delivery and penetration of skin in both animal models, suggesting that the formulation might be useful for topical therapy of skin disorders. A review of the literature59 concludes that there is insufficient evidence at present to make recommendations on the topical use of solasodine glycoalkaloids for skin cancers. Continued research on the efficacy of treatments is needed, including histologic confirmation of clearance, long-term follow-up, and comparison with surgical outcomes. Solasodine. The aglycones solasodine and tomatidine isolated from the South African medicinal plant Solanum aculeastrum Dunal inhibited the growth of HeLa, MCF7, and HT29 cancer cell lines.60 The IC50 value of the two compounds combined was lower (they were more active) than the value for solasodine but not for that of tomatidine.

Figure 4. Morphological changes induced by glycoalkaloid treatments in Hep G2 and AGS cancer cells (×400 magnification). The cells were pretreated with either α-chaconine and α-solanine (0.5 μg/mL) for 48 h and stained with sulforhodanine B (0.4% w/v) for 30 min. Morphological alterations were recorded from phase-contrast microscopic observations. Adapted from ref 2. Copyright 2005 American Chemical Society.

study demonstrated for first the time the individual and synergistic anticancer properties of the two major glycoalkaloids present in all commercial potato varieties and processed potato products (chips, fries, skins). Colon and Liver Cancer Cells. As part of an effort to improve plant-derived foods such as potatoes, eggplants, and tomatoes, the antiproliferative activities against human colon (HT29) and liver (Hep G2) cancer cells of a series of structurally related individual compounds were examined for the first time using a MTT assay.1 The objective was to assess the roles of the carbohydrate side chain and aglycone part of Solanum glycosides in influencing inhibitory activities. Evaluations were carried out with four concentrations each (0.1, 1, 10, and 100 μg/mL) of the potato trisaccharide glycoalkaloids αchaconine and α-solanine; the disaccharides β(1)-chaconine, β(2)-chaconine, and β(2)-solanine; the monosaccharide γchaconine and their common aglycone solanidine; the potato tetrasaccharide glycoalkaloid dehydrocommersonine; the potato aglycone demissidine; the tomato tetrasaccharide glycoalkaloid α-tomatine, the trisaccharide β1-tomatine, the disaccharide γ-tomatine, the monosaccharide δ-tomatine, and their common aglycone tomatidine; the eggplant glycoalkaloids α-solamargine and α-solasonine and their common aglycone solasodine; and the steroidal alkaloid jervine. All compounds were active in the assay, with the glycoalkaloids being the most active, and the hydrolysis products, less so. The effectiveness against the liver cells was greater than that against the colon cells. Potencies of α-tomatine and α-chaconine at a

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ANTICARCINOGENIC PROPERTIES OF POTATO GLYCOALKALOIDS Here, we will briefly describe reported anticarcinogenic properties and mechanisms of the bioactive potato compounds in cells (listed alphabetically) and laboratory animals. α-Chaconine. Cervical, Liver, Hepatoma, and Stomach Cancer Cells. Friedman et al.2 describe methods for the isolation of large amounts of pure α-chaconine and α-solanine from Dejima potatoes and for the extraction and analysis of total glycoalkaloid content from five fresh potato varieties (Dejima, Jowon, Sumi, Toya, and Vora Valley). These compounds were then evaluated in experiments using a MTT assay to assess the anticarcinogenic effects of (a) the isolated pure glycoalkaloids separately, (b) artificial mixtures of the two glycoalkaloids, and (c) the total glycoalkaloids isolated from each of the five potato varieties. All samples tested reduced the number of the following human cell lines: cervical (HeLa), liver (Hep G2), lymphoma (U937), and stomach (AGS and KATO III) cancer cells and normal liver (Chang) cells. The results show that (a) the effects of the glycoalkaloids were F


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Journal of Agricultural and Food Chemistry concentration of 1 μg/mL against the liver carcinoma cells were higher than those observed with the anticancer drugs doxorubicin and camptothecin. This comprehensive report on anticarcinogenic potencies of a large number of glycoalkaloids and their hydrolysis products (metabolites) seems to have stimulated worldwide interest in the anticarcinogenic properties of potato and tomato glycoalkaloids and their mechanisms of action, as indicated by the numerous studies originating from different countries described below. Colon Cancer Cells. α-Chaconine induced apoptosis of HT29 human colon cancer cells in a time- and concentrationdependent manner.61 The authors also showed that caspase-3 activity and the active form of caspase-3 were increased 12 h after α-chaconine treatment. In addition, caspase inhibitors prevented α-chaconine-induced apoptosis, whereas apoptosis was potentiated by an extracellular signal-regulated kinase (ERK) inhibitor. Results from the same study indicated that αchaconine reduced the phosphorylation of ERK. It therefore seems that α-chaconine induces apoptosis of HT-29 cells through inhibition of ERK followed by activation of caspase-3. Prostate Cancer Cells. Reddivari et al.62 found that αchaconine at 5 μg/mL and gallic acid at 15 μg/mL (a) exhibited potent antiproliferative properties and increased cyclin-dependent kinase inhibitor p27 levels in two prostate cancer cell lines, LNCaP and PC3, (b) induced poly[adenosine diphosphate (ADP)] ribose polymerase cleavage and caspase-dependent apoptosis in LNCaP cells and caspase-independent apoptosis through nuclear translocation of endonuclease G in both LNCaP and PC-3 cells, and (c) activated JNK, a response that played a major role in the induction of caspase-dependent apoptosis in LNCaP cells. These observations suggest that apoptosis induced by whole potato extracts in prostate cancer cell lines may be, in part, due to α-chaconine and gallic acid. Inhibition of Angiogenesis of Bovine Aortic Endothelial Cells. In a study by Lu et al.,63 α-chaconine inhibited the proliferation of bovine aortic endothelial cells (BAECs) in a dose-dependent manner, and nontoxic doses markedly suppressed cell migration, invasion, and tube formation. αChaconine also reduced the expression and activity of MMP2, involved in angiogenesis (blood flow to cancer cells), and potently suppressed the phosphorylation of JNK, phosphatidylinositide-3 kinase (PI3K), and Akt, but it did not affect the phosphorylation of ERK and p38. Furthermore, the authors demonstrated that α-chaconine significantly increased the cytoplasmic level of inhibitors of IκBα and decreased nuclear factor κB (NF-κB), suggesting that it could inhibit NF-κB activity. It seems that α-chaconine inhibits migration, invasion, and tube formation of BAECs by reducing MMP-2 activity and JNK and PI3K/Akt signaling pathways and inhibiting NF-κB activity, suggesting its potential for use in antiangiogenic cancer therapy. Reduction of Metastasis in Lung Carcinoma Cells. Metastasis is the spread of cancer cells from the initial or primary site of the disease to another part of the body. Shih et al.64 found that α-chaconine (a) inhibited lung adenocarcinoma A549 cell invasion, migration, and phosphorylation of c-Jun Nterminal kinase (JNK) and Akt, (b) did not affect phosphorylation of extracellular signal regulating kinase (ERK) and p38, and (c) significantly decreased the nuclear level of NF-κB and the binding ability of NF-κB, suggesting that the inhibition of cell metastasis occurs by a reduction of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities involving suppression of the phosphoinosi-

tide 3-kinase/Akt/NF-κB (PI3K/Akt/NF-κB) signaling pathway α-Solanine. Digestive System Cancer Cells. Ji et al.65 evaluated the effect of α-solanine isolated form the nightshade plant (Solanum nigrum Linn.) on the IC50 values of three digestive system tumor cell lines. The results show that (a) the IC50 values for the cell lines Hep G2, SGC-7901, and LS-174 were 14.47, >50, and >50 μg/mL, respectively, (b) the induced apoptosis rate in Hep G2 cells was 6.0, 14.4, 17.3, 18.9, and 32.2%, respectively, (c) cells in the G(2)/M phases of the cell cycle disappeared, whereas the number of cells in the S phase increased significantly for treated groups and the expression of Bcl-2 protein decreased. The target of solanine in inducing apoptosis in Hep G2 cells seems to be mediated by the inhibition of the expression of Bcl-2 protein. Liver Cancer Cells. α-Solanine markedly increased in a dosedependent manner the content of caspase-3 and concurrently decreased that of Bcl-2 in Hep G2 liver cancer cells. This observation suggests that α-solanine induces cell apoptosis by suppressing the activity of Bcl-2 and activating the caspase-3 protease.66 Studies by Ji et al.65 suggest that solanine-induced apoptosis in Hep G2 cells is turned on by reduction of the cell membrane potential, which opens ion channels that transport calcium ions down a concentration gradient, resulting in an increase in their concentration in the cell. Pancreatic Cancer Cells In Vitro and In Vivo. Studies by Sun et al.66 on the mechanism that may govern the anticarcinogenic activity of α-solanine in pancreatic cancer cells in vitro and in a nu/nu nude mouse model against human pancreatic cells show that the glycoalkaloid (a) inhibited the growth of the cancer cells through caspase-3-dependent mitochondrial apoptosis, (b) promoted the opening of the mitochondrial membrane permeability transition pore (MPTP) by downregulating the Bcl-2/Bax ratio, which resulted in the release of cytochrome c and Smac from the mitochondria into the cytosol to process the caspase-3 zymogen into its activated form, and (c) decreased the expression of tumor metastasis proteins, specifically MMP-2 and MMP-9, in the cells. In a related study, Lv et al.67 investigated the anticarcinogenic effect of α-solanine against human pancreatic cancer cells in vitro and in vivo. In vitro, α-solanine (a) inhibited the proliferation of PANC-1, sw1990, MIA PaCa-2 cells in a dosedependent manner as well as cell migration and invasion at nontoxic doses; (b) suppressed the expression of MMP-2/9, extracellular inducer of matrix metalloproteinase CD44, eNOS, and E-cadherin in PANC-1 cells, (c) significantly decreased vascular endothelial growth factor (VEGF) expression and tube formation of endothelial cells, (d) suppressed phosphorylation of Akt, mTOR, and Stat3, and (e) enhanced phosphorylation of β-catenin and markedly decreased tran-nuclear translocation of NF-κB, β-catenin, and TCF-1. In vivo, administration of αsolanine (6 μg/g for 2 weeks) in a xenograft mouse model induced decreases in tumor volume and weight by 61 and 43%, respectively, as well as MMP-2/9, proliferating cell nuclear antigen (PCNA), and VEGF expression. These results indicate that the beneficial in vitro and in vivo effects seem to occur via the suppression of proliferation, angiogenesis, and metastasis. It seems that solanine might be an effective compound for the treatment of human pancreatic cancer. Prostate Cancer Cells. An in vitro investigation of the effects of α-solanine on human androgen-independent prostate cancer cell line PC-3 showed that α-solanine suppressed the growth of the cells in a dose- and time-dependent manner and that the G


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Journal of Agricultural and Food Chemistry cells were arrested in S phase.68 The protein level of IκBα was increased and that of Bcl-2 was decreased at all tested concentrations (30, 40, and 50 μg/mL), suggesting that the antiprostate cancer effect occurred via inhibition of cell proliferation, arrest of the cells in S phase, induction of apoptosis, upregulation of the expression of IκBα, and downregulation of Bcl-2. Shen et al.69 investigated the mechanism involved in the suppression of human prostate cancer cell line (PC-3) metastasis by α-solanine. The results show that α-solanine reduces the viability of PC-3 cells. Treatment with a nontoxic dose markedly suppresses cell invasion and significantly elevates the expression of epithelial marker E-cadherin, and it concomitantly decreases the expression of mesenchymal marker vimentin, suggesting that the glycoalkaloid suppresses the epithelial−mesenchymal transition (EMT). The authors also showed that α-solanine reduces the mRNA level of MMP-2, MMP-9, and extracellular inducer of matrix metalloproteinase (EMMPRIN), but it increases the expression of reversioninducing cysteine-rich protein with kazal motifs (RECK) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. In addition, it suppresses the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, and ERK. Furthermore, αsolanine downregulates oncogenic microRNA-21 (miR-21), upregulates tumor suppressor miR-138 expression and reduces ERK and PI3K/Akt signaling pathways, and regulates expression of miR-21 and miR-138. It seems that the inhibition of PC-3 cell invasion by α-solanine might, in part, result from blocking EMT and the expression of MMPs. These findings have therapeutic potential for suppressing invasion of prostate cancer cells. Inhibition of Breast Cancer in Mice. Mohsenikia et al.70 investigated α-solanine toxicity in vitro and in vivo and assessed its protective and therapeutic effects on a typical mouse model of breast cancer. The results show that α-solanine significantly suppressed the proliferation of mouse mammary carcinoma cells both in vitro and in vivo; at a concentration of 5 mg/kg, the tumor rate in the treated group was 0 compared with a 75% rate in the untreated controls. The average tumor size and weight were significantly lower in treated mice than that in corresponding controls. Moreover, α-solanine induced an increased in Bax protein expression in the breast tumor compared with that its respective control group and induced decreased expression of the antiapoptotic Bcl-2 protein and a decrease in proliferative and angiogenic parameters. These results demonstrate the chemoprotective and chemotherapeutic potential of α-solanine in a breast cancer model that operates through apoptosis induction and cell proliferation and angiogenesis inhibition. Inhibition of Human Melanoma Cell Migration and Invasion. Lu et al.71 examined the effect of α-solanine on the metastasis of melanoma cancer cells in vitro. The results show that α-solanine (a) inhibited proliferation of human melanoma cell line A2058 in a dose-dependent manner, (b) markedly suppressed cell migration and invasion and reduced the activity of MMP-2 and MMP-9, involved in the migration and invasion of cancer cells, at a nontoxic dose, (c) potently suppressed the phosphorylation of JNK, PI3K, and Akt but did not affect phosphorylation of extracellular signal regulating kinase (ERK), and (d) significantly decreased the nuclear level of NF-κB and inhibited NF-κB activity. Collectively, the results suggest that αsolanine inhibited migration and invasion of A2058 cells by

reducing MMP-2/9 activities and inhibiting JNK and PI3K/Akt signaling pathways and NF-κB activity. Disruption of Cell Membranes. Hep G2 cells treated with αsolanine showed typical signs of apoptosis associated with a lowered membrane potential of the mitochondria and an increased concentration of Ca2+.72 It seems that α-solanine opens up channels in the membrane by lowering the membrane potential that then leads to the transport of Ca2+ ions down their concentration gradient, resulting in an increase in the concentration of calcium ions in the cell and initiating the mechanism apoptosis. Solanidine. Solanidine and Solanidine Analogues. Here, we will mention several aspects of solanidine biology and chemistry that may be relevant to the theme of the present review. A structure−function relationship study of the biological activities (cell cycle arrest, apoptosis) on human osteosarcoma 1547 cells revealed a correlation between the experimental and theoretical data that highlighted the importance of the heterosugar moiety and the 5,6 double bond in these activities.73 Six synthetic solanidine analogues exhibited strong anticancer activities and multidrug resistance reversal effects in a hypodiploid population of HeLa murine lymphoma cells, suggesting that the modified solanidine skeleton is a suitable substrate for the design and synthesis of further innovative drug candidates with anticancer activities.52 Inhibition of Multidrug Resistance. Because intrinsic or acquired resistance of tumor cells to multiple cytotoxic drugs (multidrug resistance, MDR) is a major cause of failure of cancer chemotherapy, Lavie et al.74 examined the ability of steroidal alkaloids of plant origin, namely, the Veratrum sp. alkaloid cyclopamine and the Lycopersicon sp. Aglycone (alkaloid) tomatidine, to act as chemosensitizers in multidrug-resistant NCI AdrR human adenocarcinoma. The results show that the alkaloids inhibited P-gp-mediated drug transport and multidrug resistance, suggesting that these plant-derived compounds may serve as chemosensitizers in combination chemotherapy with conventional cytotoxic drugs for treating multidrug-resistant cancer.

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ANTICARCINOGENIC PROPERTIES OF THE TOMATO GLYCOALKALOID TOMATINE Here, we will briefly mention results of reported studies on the anticarcinogenic potential of α-tomatine in vitro and in vivo. Early Studies on the Inhibition of Multiple Cancer Cells. Lee et al.,1 using the MTT in vitro assay, found that commercial tomatine is a strong inhibitor of growth for both human colon and liver cancer cell lines, as evidenced by the dose-dependent (0.1−100 μg/mL) inhibition of HT29 colon cancer cells at levels ranging from 38.0 to 81.5% and of human Hep G2 liver cancer cells from 46.3 to 89.2%. The anticarcinogenic activity against human liver cancer cells at a tomatine concentration of 1 μg/mL was higher than the activity observed with the commercial anticancer drug doxorubicin. Friedman et al.75 also investigated six green and three red tomatoes extracts for their ability to induce cell death in human cancer and normal cells using a microculture MTT assay. Compared to the untreated controls, the high-tomatine green tomato extracts strongly inhibited the following human cancer cell lines: breast (MCF-7), colon (HT-29), gastric (AGS), and hepatoma (liver) (Hep G2) as well as normal human liver cells (Chang). In another study, we discovered that the activity of αtomatine generally decreases upon removal of one or more of the four carbohydrate groups of the lycotetraose side chain.76 H


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Journal of Agricultural and Food Chemistry For example, the activity of α-tomatine against the PC-3 prostate cancer cells was about 200 times greater than that of the aglycone tomatidine. Tomatidine is, however, active against the foodborne pathogen Staphylococcus aureus,77 suggesting that the two bioactivities seem to be governed by different mechanisms. Our systematic studies on the bioactivity of tomatine at microgram levels against multiple human cancer cells seems to have stimulated interest from a number of investigators mentioned below to explore the biomarkers and associated signaling pathways that may be associated with the anticarcinogenic effects of tomatine. Leukemia Cells. α-Tomatine inhibited human leukemia MOLT-4 cells by activating cell cycle checkpoints without damaging single or double DNA strands in the cells.78 The slowing of the cell cycle seems to involve caspase-independent cell death associated with an increase in the tumor suppressor protein p53 and the proapoptotic protein PUMA (p53 upregulated modulator of apoptosis) as well as other biomarkers associated with cell cycle regulation. A related study found that α-tomatine-mediated anticancer activity against human chronic myeloid leukemia cells in vitro and in a transplanted mouse tumor operated through cell cycle- and caspase-independent pathways.79 Prostate Cancer Cells. α-Tomatine inhibited PC-3 prostate cancer cells with an IC50 value of 1.67 μM.80,81 Cytotoxicity occurred after an hour of treatment and was mainly due to induction of apoptosis, as evidenced by decreased mitochondrial membrane potential, increased nuclear condensation, polarization of F-actin potential, cell membrane permeability, cytochrome c expression, induction of activation of caspase-3, -8, and -9, inhibition of NF-κB nuclear translocation, and a decrease in NF-κB/p50 and NF-κBp65 in the nuclear fraction. Suppression of NF-κB activation by α-tomatine in PC-3 prostate cancer cells seems to occur through the inhibition of IκBα kinase activity, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, NF-κB/p65 phosphorylation, and NF-κB p50/p65 nuclear translocation.82 As expected, α-tomatine also reduced TNF-α-induced activation of the prosurvival mediator Akt. Its inhibition of NF-κB activation was accompanied by significant reduction in the expression of NFκB-dependent antiapoptotic (c-IAP1, c-IAP2, Bcl-2, Bcl-xL, XIAP, and survivin) proteins. It seems that NF-κB plays a role in prostate cancer and that agents that suppress its activation may inhibit development or progression of this malignancy. Inhibition of Lung Cancer Cell Migration and Invasion. Shih et al.83 found that α-tomatine (a) inhibited cell invasion, migration, and phosphorylation of Akt and extracellular signal-regulated kinase 1 and 2 (ERK1/2) in human lung adenocarcinoma A549 cells, (b) did not affect phosphorylation of JNK and p38, (c) decreased nuclear levels of NF-κB, c-Fos, and c-Jun, and (d) inhibited the binding abilities of NF-κB and activator protein-1 (AP-1). Metastasis inhibition occurs by reducing the effects of MMP-2, MMP-9, and uPA (urokinase-type-plasminogen activator) through the PI3K/Akt or ERK1/2 signaling pathway and inhibiting NF-κB or AP-1 binding activities. A related study84 confirmed that α-tomatine suppressed invasion and migration of human non-small-cell lung cancer NCI-H460 cells through inactivation of the FAK/PI3K/Akt signaling pathway and lowering the binding activity of NF-κB. Cytotoxicity occurred through inactivation of the signaling

pathway and enhancement of IkBα protein expression to reduce NF-κB DNA binding activity, resulting in the downregulation of MMP-7 expression, inhibition of cell migration, and interference with the rearrangement of the actin cytoskeleton by decreasing the expression of the pFAK protein. Inhibition of Fish and Mouse Tumors. Feeding 2000 ppm of tomatine and 224 ppm of the multiorgan carcinogen dibenzo[a,l]pyrene (DBP) to rainbow trout for 9 months resulted in a reduced incidence of liver and stomach tumors by 41.3 and 36.3%, respectively, as compared to the incidence of tumors observed with DBP alone.85 This seems to be the first report on the inhibition of tumor growth by dietary α-tomatine. Intraperitoneally (ip) administered α-tomatine (5−10 mg/ kg) significantly attenuated the growth of androgen-independent PC-3 prostate cancer cells in mice.82 Tumor suppression was associated with increased apoptosis and with reduced nuclear translocation of the p50 and p65 components of the NF-κB signaling pathway. It seems that α-tomatine can inhibit the growth of prostate cancer tumors in vivo without inducing overt toxicity. An evaluation of the antitumor activity of α-tomatine against PC-3 cell tumors grown subcutaneously and orthotopically in mice showed that ip administration of α-tomatine significantly attenuates the growth of PC-3 cell tumors grown at both sites.82 Analysis of tumor material indicates that the tumorsuppressing effects were accompanied by increased apoptosis and lower proliferation of tumor cells as well as reduced nuclear translocation of the p50 and p65 components of NF-κB. Intraperitoneal-injected α-tomatine at 1 mg/kg slowed the growth of mammary carcinoma (Ehrlich tumors) in mice.86 The combination of α-tomatine (1 mg/kg) and the cancer drug doxorubicin (2 mg/kg) acted synergistically and extended survival of the mice with the Ehrlich tumors. The activity against the tumors, which are derived from adenocarcinoma of the mammary gland, seems to involve the immune system in the inhibition of tumor progression. This suggestion seems plausible based on reports by other investigators that tomatine contributes to the protective immunity of rodents (see below). Kim et al.87 determined the effect of commercial α-tomatine on CT-26 colon cancer cells in vitro and in vivo in an intracutaneously transplanted mouse tumor. Cytotoxicity experiments showed that α-tomatine induces about 50% lysis of the cancer cells at 3.5 μM after 24 h treatment. Large proportions of cells were found to be in the Annexin V (+)/propidium iodide (+) phase of cell death, implying latephase apoptotic/necrotic status. α-Tomatine induced cell death in CT-26 cancer cells through caspase-independent signaling pathways. This conclusion was supported by western blot analysis showing localization of apoptosis-inducing mitochondrial protein (AIF) in the nucleus, downregulation of the apoptosis inhibitor survivin, and failure to detect the active form of caspase-3, -8, and -9 produced by proteolytic cleavage in CT-26 cancer cells. The ip-administered α-tomatine (5 mg/kg body weight) also markedly inhibited growth of the tumor without causing body and organ weight changes. It seems that the reduced tumor growth in the mice by 38% after 2 weeks was the result of increased caspase-independent apoptosis associated with increased nuclear translocation of AIF and decreased survivin expression in tumor tissues. It seems that α-tomatine in pure form and in tomatine-rich green tomatoes might prevent colon cancer. I


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disruption of cancer cell membranes associated with changes in ion flux and interstitial currents of the membranes may contribute to the anticarcinogenic mechanisms governing their action in animal and human cells in vitro and in vivo. In a related study involving membrane potentials, Taveira et al.100 found that tomatine-containing tomato leaf extracts and the isolated α-tomatine and tomatidine pure compounds at nontoxic concentrations preserved the mitochondria membrane potential, decreased reactive oxygen species of SY5Y glutamateinsulted neuronal cells, and interacted with nicotinic receptors. The authors suggest that this study provides novel insights into the neuroprotective effect of glutamate-induced neurotoxicity and demonstrates the low toxicity of both compounds.

In addition to the cited mechanistic aspects involving proapoptotic biomarkers and signaling pathways, it seems likely that tomatine−cholesterol interactions, tomatine-induced stimulation of the immune system, and disruption of cancer cell membranes might also contribute to the mechanisms that govern its anticarcinogenicity. We will now briefly mention the possible scientific basis for these suggestions. Stimulation of the Immune System. α-Tomatine can act as a powerful adjuvant to elicit an antigen-specific cell-mediated immune response to the circumsporozoite (CS) protein, a major pre-erythrocyte stage malaria vaccine candidate antigen, requiring both CD80 and CD86 costimulation to form antigenspecific cellular immunity.88 Heal et al.89 found that α-tomatine contributed to protective immunity elicited by a malaria vaccine candidate via CD8+ T cell release of antigen-specific IFN-γ in a Plasmodium berghei (malaria) rodent model. It seems that stimulation of the immune system might also contribute the anticarcinogenic effects of α-tomatine. α-Tomatine−Cholesterol Interactions in Breast and Leukemia Cancer Cells. Sucha et al.90 observed that the inhibition of cell proliferation and viability of human breast adenocarcinoma MCF-7 cells in culture at concentrations of 6 and 9 μM was followed by a recovery of cells. The recovery was not caused by the biotransformation of α-tomatine in the cells but by a substantial decrease in the concentration of α-tomatine in the culture medium due to its binding with cholesterol. Additional experiments on the regulation of the mechanism of action of α-tomatine revealed a loss of ATP in α-tomatinetreated cells but no DNA damage, no changes in the levels of the proteins p53 and p21(WAF1/Cip1), and no apoptosis (neither activated caspase-8 and -9, sub-G1 peak, nor morphological signs). The authors suggest that these results support the conclusion that α-tomatine does not induce apoptosis in the MCF-7 cell line in culture. Another study found that treatment of human myeloid leukemia HL-60 cells with α-tomatine resulted in growth inhibition and apoptosis in a concentration-dependent manner, that both events were partially abrogated by added cholesterol, and that α-tomatine inhibited the growth of HL-60 xenografts in vivo.91 The authors suggest that interactions between αtomatine and cell membrane-associated cholesterol might be involved in mediating the in vivo anticarcinogenic effect of αtomatine. These results and the reported strong affinity of αtomatine to cholesterol in an artificial cell membrane,92 and to plasma cholesterol in vivo,93−96 imply that the affinity of the glycoalkaloid to cancer cell membrane cholesterol might be a factor governing the mechanism of apoptosis. Disruption of Cell Membranes. As part of an effort designed to establish the mechanism of action of glycoalkaloids in cells, frog embryos and frog skin were exposed to varying concentrations of α-tomatine and tomatidine.97 α-Tomatine increased the fluorescence-measured membrane permeability of frog embryos by about 600% compared with control values; the corresponding value for tomatidine was about 150%. The glycoalkaloid also diminished sodium-active transport in frog skin by about 16% compared with control values, as estimated from the change in the interstitial short-circuit current. Tomatidine had no effect on frog skin. These observations suggest that the sugar side chain present in α-tomatine but not in tomatidine influences membrane permeability of cells. As these findings complement similar results with glycoalkaloids from potatoes98,99 and eggplants,39 it is likely that the

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DIETARY SIGNIFICANCE AND RESEARCH NEEDS Overall, the cited studies seem to indicate that the molecular, signaling, biomarker, immunomodulating, cholesterol-chelating, and membrane-disruptive events at the cellular and molecular levels associated with apoptosis and cell migration and invasion might not be the same for the different cancer cell lines. They imply that both intrinsic and extrinsic proapoptosis pathways are involved and that α-tomatine may protect against the development and progression of several cancers (multiorgan protection). This is not surprising because, as mentioned earlier, carcinogenesis is a sequential multistage cellular process consisting of tumor initiation, promotion, and progression, characterized by dysregulation of multiple genes resulting in multiple adverse symptoms. Each stage involves signaling pathways and both the same and different associated biomarkers. The structurally different glycoalkaloids and their aglycones might impact the cancer cell components at different rates. Antineoplastic glycoalkaloids complement and extend our knowledge of the mechanisms of alterations in the gene and/or protein levels of the Bcl-2 family members and other cell death mechanisms that are active in cancer cells following treatment with glycoalkaloids and numerous other natural compounds.101,102 This overview is intended to stimulate interest in the use of both pure and food-containing glycoalkaloids at nontoxic levels to help protect against or ameliorate multiorgan carcinogenesis. With respect to potatoes, unofficial worldwide guidelines recommend a guideline for total glycoalkaloid content of 20 mg/100 g fresh weight.6,7 On the basis of the anticarcinogenic results discussed earlier, it seems that this level in commercial potatoes might help to protect against multiple cancers. Epidemiological studies are, however, needed to demonstrate this possibility. Guidelines for maximum glycoalkaloid content of eggplants and tomatoes have not been established. Because, compared to the other glycoalkaloids, tomatine exhibits low toxicity in animals and humans, future experimental and epidemiological studies should concentrate on the tomato compounds.4,25 Plant scientists are challenged to develop high-tomatine red tomatoes. High-tomatine red tomatoes will contain two anticarcinogenic compounds: the antioxidative red pigment lycopene and tomatine.103 The potential payoff will be better human health. Future studies need to address the following additional food and medical aspects: • Determine whether in vitro anticarcinogenic effects of pure glycoalkaloids and glycoalkaloid-containing plant foods can be duplicated in humans. J



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• Determine how bioactivities vary depending on whether glycoalkaloids are tested or consumed in the free-state or as part of a mixture or a food. • Determine, using epidemiology, the presumptive connection between glycoalkaloid consumption and lower risk of cancer in humans. • Determine whether glycoalkaloid metabolites formed after absorption into the circulation possess anticarcinogenic properties. • Validate, via dietary interventions, predicted anticarcinogenic properties based on mathematical modeling104 or molecular interaction networks.105 • Define additive and synergistic effects of glycoalkaloids with other anticarcinogenic food-related plant foods and bioactive compounds, including pigmented rice brans and its anticarcinogenic constituent γ-oryzanol;106−110 black and green teas and their anticarcinogenic epigallocatechin gallate (ECGC) and theaflavin constituents;111−113 mushroom polysaccharides;29,114 and multifunctional jujube fruit (Chinese dates) and jujube fruit and seed compounds jujuboside B and betulinic acid.115−118 It seems that consumption of glycoalkaloidcontaining food, pigmented rice, and teas with a high content of catechins and theaflavins might ameliorate carcinogensis119−121 and that tea flavonoids might alleviate both cancer and infectious disease;122 as noted above, lycopene- and tomatine-containing tomatoes might mitigate both carcinogenesis and cardiovascular disease. Combinations of food and bioactive food ingredients that act additively or synergistically will decrease the amounts needed for effective, safe, and tasty food formulations. • Evaluate the efficacy of glycoalkaloids against multidrugresistant cancers. • Because inhibition of hedgehog signaling decreases tumor growth, determine whether inhibition of hedgehog signaling by tomatidine or tomatine can help to inhibit carcinogenesis.123,124 • Will α-tomatine, which is reported to inhibit the herpes simplex virus via insertion into the viral envelope, also inhibit the human papillomavirus that causes cervical cancer?125,126 • Encourage growers to produce tomatoes with a high content of tomatine using antisense RNA methods to suppress the genes that degrade tomatine. Create tomatine-containing potatoes.127−130 • Determine the anticarcinogenic potential of numerous glycoalkaloids present in tubers, leaves, and sprouts of uncultivated and wild-type potatoes.131−137 • Do glycoalkaloids contribute to the anticarcinogenic properties of anthocyanin-rich color-fleshed and highantioxidant potatoes?138,139

ACKNOWLEDGMENTS I take great pleasure in thanking my collaborators whose names appear in the cited references and Carol E. Levin for facilitating the preparation of the manuscript.

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ABBREVIATIONS USED AIF, apoptosis-inducing factor; AK, actinic keratosis; Akt, protein kinase B; Annexin V-FITC, annexin V conjugated with fluorescein isothiocyanate, for detection of cell apoptosis; AP-1, activator protein-1; Bax, a proapoptotic proteins; BCC, basal cell carcinoma; Bcl-2, Bcl-xL, antiapoptotic proteins; BAEC, bovine aortic endothelial cells; c-Fos, apoptosis signaling protein; c-IAP1, c-IAP2, antiapoptotic proteins; DBP, dibenzo[a,l]pyrine-carcinogen; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; Fas, proapoptotic protein; EMT, epithelial mesenchymal transition; IC50, concentration of the test substance that inhibited 50% of the cancer cells; IFN-γ, interferon-gamma; IgG, immunoglobulin; ip, intraperitoneal; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; MAPK, mitogen-activated protein kinase; MDR, multidrug resistance; miR-21, microRNA-21; MMP, matrix metalloproteinase; MPTP, mitochondrial membrane permeability transition pore; MTT, a tetrazolium dye, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NP-40, Tergitol-type NP-40 detergent; NSCLC, non-small-cell lung cancer; PCNA, proliferating cell nuclear antigen; P-gp, pglycoprotein; PI, propidium iodide; PS, phosphatidylserine; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PI3K/ AKT/mTOR, an intracellular signaling pathway; PUMA, proapoptotic protein; RECK, reversion-inducing cysteine-rich protein with kazal motifs; SCC, squamous cell carcinoma; TCF-1, transcription protein; TFNR-I, TFNR-II, tumor necrosis factor receptors; TIMP-1, tissue inhibitor of metalloproteinase-1; TNF-α, TNF-β, tumor necrosis factors; VEGF, vascular endothelial growth factor; uPA, urokinase type plasminogen activator; XIAP, X-chromosome-linked inhibitor of apoptosis

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REFERENCES

(1) Lee, K.-R.; Kozukue, N.; Han, J.-S.; Park, J.-H.; Chang, E.-Y.; Baek, E.-J.; Chang, J.-S.; Friedman, M. Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. J. Agric. Food Chem. 2004, 52, 2832−2839. (2) Friedman, M.; Lee, K. R.; Kim, H. J.; Lee, I. S.; Kozukue, N. Anticarcinogenic effects of glycoalkaloids from potatoes against human cervical, liver, lymphoma, and stomach cancer cells. J. Agric. Food Chem. 2005, 53, 6162−6169. (3) Friedman, M.; McDonald, G. M. Potato glycoalkaloids: chemistry, analysis, safety, and plant physiology. Crit. Rev. Plant Sci. 1997, 16, 55−132. (4) Friedman, M. Tomato glycoalkaloids: role in the plant and in the diet. J. Agric. Food Chem. 2002, 50, 5751−5780. (5) Friedman, M. Analysis of biologically active compounds in potatoes (Solanum tuberosum), tomatoes (Lycopersicon esculentum), and jimson weed (Datura stramonium) seeds. J. Chromatogr. 2004, 1054, 143−155. (6) Friedman, M. Potato glycoalkaloids and metabolites: roles in the plant and in the diet. J. Agric. Food Chem. 2006, 54, 8655−8681. (7) Friedman, M.; Levin, C. E. Glycoalkaloids and calystegine alkaloids in potatoes. In Advances in Potato Chemistry and Technology, 2nd ed.; Singh, J., Kaur, L., Eds.; Academic Press: Boston, MA, 2015. (8) Das, M.; Barua, N. Pharmacological activities of Solanum melongena Linn. (Brinjal plant). Int. J. Green Pharm. 2013, 7, 274−277.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Phone: 510-5595615. Notes

The author declares no competing financial interest. K


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