Pomegranate Vascular Remodeling

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The pomegranate's medicinal qualities have been known for thousands of years. References in the Bible and Roman mythology mention the tree's unique healing powers, and some Middle Eastern, Asian, and South American people still chew its bark, petals, and peel to treat conditions as diverse as dysentery and diseases of the mouth and gums.1 Modern research has shown that the pomegranate contains polyphenols and anthocyanidins that are powerful free-radical scavengers and are more effective against disease than are those in red wine and green tea.2 It is widely used in traditional medicine to cure inflammation, diabetes, cardiac disease, AIDS, ischemia, and cancer (Figure 6.1). On this basis, the possible anticarcinogenic effects of the pomegranate have been further explored. For example, the application of pomegranate extract to the skin of mice before they were exposed to a carcinogenic agent was shown to inhibit the appearance of erythemas and hyperplasia and the activity of epithelial ornithine decarboxylase.2 The pomegranate has also been shown to induce programmed cell death and to inhibit tumor invasion, proliferation, and angiogenesis. It targets several proteins in the cell-signaling pathway (Figure 6.2). The current review, therefore, will focus on the anticancer potential of the pomegranate and its components.

MMPs

MMPs

FIGURE 6.1 Disease targets of pomegranate.

Coronary heart disease

Coronary heart disease

FIGURE 6.2 Molecular targets of pomegranate. (MMPs, matrix metalloproteinases; VEGF, vascular endothelial growth factor; LOX, lipoxygenase; MAPK, mitogen-activated protein kinase; MIF, migration inhibitory factor; JNK, c-Jun N-terminal kinase; ERK1/2, extracellular signal regulated kinase.)

6.2 CHEMICAL COMPONENTS OF THE POMEGRANATE

The unique biochemistry of the pomegranate tree is quite intriguing. In addition to the high levels of antioxidant-rich tannins and flavonoids in its juice and peel, the crushed and dry seeds of its fruit produce a distinct oil, about >60% of which is a very rare 18-carbon fatty acid, also referred to as punicic acid. This oil contains isoflavone genistein, the phytoestrogen coumestrol, and the sex steroid estrone. In fact, the pomegranate tree is one of the only plants in nature known to contain estrone.3 Its estrone-containing nature may in part explain its therapeutic efficacy, given that several lines of evidence suggest a possible role of phytoestrogens in preventing a range of diseases, not least of which are the hormonally dependent cancers. Online biochemical detection coupled with mass spectrometry has revealed three estrogenic compounds — luteolin, quercetin, and kaempferol — in pomegranates.3 Other major components of pomegranate juice are ellagic acid, caffeic acid, and punicic acid; all are found in the aqueous or oily compartments of the pomegranate fruit, and each belongs to a different representative chemical class with known anticancer activities.

Anthocyanidins are components of pomegranate fruit that contribute to the antioxidant activity. Anthocyanidins (delphinidin, cyanidin, and pelargonidin) have been shown to have free-radical scavenging activities and inhibitory effects on lipid peroxidation. They inhibit hydrogen peroxide-induced lipid peroxidation in the rat brain homogenates.4 Evidence suggests that polyphenolic antioxidants contained in pomegranate juice can contribute to the reduction of oxidative stress and atherogen-esis through the activation of redox-sensitive genes ELK-1 and p-JUN and increased eNOS expression.5

6.3 ANTITUMOR EFFECTS OF THE POMEGRANATE

Various parts of the pomegranate fruit have been shown to exert antiproliferative effects on tumor cells. For example, the polyphenols in the fermented juice of pomegranates have been shown to exert anticancer effects on human breast cancer cells in vitro.3 Mehta et al. further showed that whole pomegranate seed oil is even more chemopreventive against breast cancer than are these polyphenols.6 In their study of the chemopreventive and adjuvant therapeutic potential of pomegranate components in human breast cancer, Kim et al.7 found that all the components blocked endogenous active estrogen biosynthesis and aromatase activity by 60 to 80%. The inhibition of cell lines by fermented juice and pericarp polyphenols was highest in estrogen-dependent MCF-7 cells, somewhat lower in estrogen-independent MDA-MB-231 cells, and lowest in normal human breast epithelial MCF-10A cells. In both MCF-7 and MDA-MB-231 cells, fermented pomegranate juice polyphenols consistently showed approximately twice the antiproliferative effect that fresh pomegranate juice polyphenols showed. In addition, pomegranate seed oil effected a 90% inhibition of proliferation of MCF-7 cells at 100 ^g/ml medium, a 75% inhibition of invasion of MCF-7 cells across a Matrigel membrane at 10 ^g/ml, and a 54% apoptosis in MDA-MB-435 estrogen receptor-negative metastatic cells at 50 ^g/ml. Furthermore, in a murine mammary gland organ culture, fermented juice polyphenols effected a 47% inhibition of cancerous lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene. These observations support the adjuvant therapeutic application of pomegranate in human breast cancer.7

The seed oil, juice, fermented juice, and peel extract of the pomegranate have also been shown to exert suppressive effects on human breast cancer cells in vitro.8 Lansky et al. examined the various dissimilar biochemical fractions originating in anatomically discrete sections of the pomegranate fruit for their synergistic effect against the proliferation, metastatic potential, and phospholipase A2 expression of human prostate cancer cells in vitro.9 They found that these fractions had supraadditive, complementary, and synergistic effects.9 Similarly, Albrecht et al. examined the effects of pomegranate seed oil, fermented juice polyphenols, and pericarp polyphenols on the growth of human prostate cancer cell xenografts in vivo and on the cells' proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel in vitro. All the three components acutely inhibited the in vitro proliferation of LNCaP, PC-3, and DU 145 human prostate cancer cell lines but had much less profound effect on normal prostate epithelial cells. These effects were mediated by changes in both the cell cycle distribution and the induction of apoptosis. In particular, all agents potently suppressed PC-3 invasion through Matrigel and PC-3 xenograft growth in athymic mice.10

Pomegranate fruit extract treatment of highly aggressive human prostate cancer PC-3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. The antiproliferative effects of pomegranate fruit extract (PFE) involves the induction of proapoptotic gene products, Bax and Bak and down-regulation of the antiapoptotic genes Bcl-XL and Bcl-2. PFE treatment also led to induction of WAF1/p21, KIP1/p27, and a decrease in cyclins D1, D2, E; and cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. Oral administration of PFE to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels.11

Several studies demonstrate that cholesterol accumulates in solid tumors and that cholesterol homeostasis breaks down in the prostate with aging and with the transition to the malignant state.12 Pomegranate juice has been demonstrated to inhibit the biosynthesis of cholesterol in macrophage cells.13 These observations suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer.

Pomegranate juice, ellagic acid, punicalagin, and total pomegranate tannins have been shown to induce apoptosis in HT-29 colon cells.14 However, in HCT116 colon cells, apoptosis was induced by ellagic acid, punicalagin, and total pomegranate tannin but not by pomegranate juice.14 Pomegranate seed oil is composed of more than 70% of the conjugated linolenic acids shown to suppress colon carcinogenesis. Not surprisingly, then, dietary pomegranate seed oil significantly inhibited the incidence of azoxymethane-induced colonic adenocarcinomas.15

Excessive human exposure to solar ultraviolet (UV) radiation, particularly to its UV-B component, causes many adverse effects, including erythema, hyperplasia, hyperpigmentation, immunosuppression, photoaging, and skin cancer, that the pomegranate can counter. In this regard, the anthocyanidins (such as delphinidin, cyanidin, and pelargonidin) and hydrolyzable tannins (such as punicalin, pedunculagin, puni-calagin, and gallagic and ellagic acid esters of glucose) in the pomegranate possess strong antioxidant and anti-inflammatory properties that protect from ultraviolet radiation. In addition, the pomegranate fruit extract (PFE) has been shown to inhibit UV-B-mediated phosphorylation of mitogen-activated protein kinase and nuclear factor (NF)-kB activation.16 The dermal application of PFE also suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion in 7,12-dim-ethylbenz(a)anthracene-initiated CD-1 mice.17 Compared with mice that did not receive PFE, the animals pretreated with the extract showed a substantially reduced tumor incidence and a lower total body tumor burden when assessed according to the total number of tumors per group, the percentage of mice with tumors, and the number of tumors per animal.

Pomegranate seed oil has also been shown to significantly decrease tumor incidence, tumor multiplicity, and TPA-induced ornithine decarboxylase activity in a two-stage skin carcinogenesis model in mice. These results highlight the potential of pomegranate as a safe and effective chemopreventive agent against skin cancer.17 Flavonoid-rich polyphenol fractions from the pomegranate fruit also exert anti-proliferative, anti-invasive, antieicosanoid, and proapoptotic effects on breast and prostate cancer cells and have antiangiogenic activities in vitro and in vivo. For example, the flavonoid-rich fractions from pomegranate juice were shown to be potential differentiation-promoting agents of human HL-60 promyelocytic leukemia cells.18 In addition, the effect of the boiled extract of pomegranate peel was examined in the human cell lines Raji and P3HR-1. The proliferation and viability of these tumor cells were dose-dependently reduced by the pomegranate extract. Collectively, these studies confirm the potent antitumor effects of the various components of the pomegranate fruit.8

6.4 EFFECT ON NF-kB ACTIVATION

The various components of the pomegranate have been tested for their effects on NF-kB. NF-kB is a transcription factor that is activated in response to various stimuli, including cytokines, mitogens, carcinogens, chemotherapeutic agents, endotoxin, physical and chemical stresses, radiation, hypoxia, and other inflammatory stimuli. Furthermore, constitutively active NF-kB is frequently encountered in a wide variety of tumors. NF-kB activation has been shown to regulate the expression of over 200 genes involved in cellular transformation, proliferation, antiapoptosis, angiogenesis, invasion, and metastasis. Whereas most carcinogens and tumor promoters activate NF-kB, chemopreventive agents can suppress this activation. For example, the activation of NF-kB in vascular endothelial cells in response to biochemical or biome-chanical stimuli is associated with vascular pathologies such as atherosclerosis; however, pomegranate wine has been shown to inhibit tumor necrosis factor a-(TNF) or shear stress-mediated NF-kB activation in vascular endothelial cells.19

Afaq and colleagues examined the effect of PFE on UV-B-induced adverse effects in normal human epidermal keratinocytes (NHEK). The treatment of NHEK with PFE (10 to 40 ^g/mL) for 24 h before UV-B (40 mJ/cm2) exposure inhibited UV-B-mediated phosphorylation of extracellular signal regulated kinase (ERK)l/2, c-jun N terminal kinase (JNK) 1/2, and p38 mitogen activated protein kinase in a dose-dependent manner. PFE treatment of NHEK also resulted in a dose- and time-dependent inhibition of UV-B-mediated degradation and phosphorylation of iKBa and in activation of IKKa. It was also shown that PFE treatment of NHEK resulted in a dose- and time-dependent inhibition of UV-B-mediated nuclear translocation and phosphorylation of NF-KB/p65 at Ser(536).1620 Additionally, in the HT-29 human colon cancer cell line, PFE was shown to reduce TNFa-induced phosphorylation of the p65 subunit and binding to the NF-kB response element 6.4-fold. TPT suppressed

NF-kB binding 10-fold, punicalagin 3.6-fold where ellagic acid (another major pomegranate component) was ineffective. In this same study, PFE also abolished TNFa-induced activation of AKT, a kinase involved in the induction of NF-kB activity (unpublished data). Moreover, in our study of the effects of the various pomegranate components on NF-kB and AKT activation, we found that pomegranate juice, total pomegranate tannins, and punicalagin suppressed NF-kB and AKT activation, leading to inhibition of cyclooxygenase-2 (COX-2) expression and of cellular proliferation in colon cancer cells (unpublished data). Therefore, the anti-inflammatory properties of polyphenolic phytochemicals in the pomegranate can play an important role in the modulation of inflammatory cell survival signaling.

6.5 EFFECT ON COX-2

COX-2 is an enzyme induced by inflammatory and mitogenic stimuli and causes enhanced synthesis of prostaglandins in inflamed and neoplastic tissues. It is associated with cell proliferation and growth in various cancerous conditions and is a regulatory factor for several pathways that can result in cancer. Additionally, COX-2 makes cells resistant to apoptosis and promotes angiogenesis, metastasis, and the cancer cell cycle by controlling several targets.

Afaq et al. found that the topical application of PFE (2 mg/mouse) 30 min before TPA application to mouse skin (3.2 nmol/mouse) inhibited the TPA-mediated increase in the protein expression of COX-2 in a time-dependent manner.20 Likewise, Schubert et al. found in their examination of the antioxidant and eicosanoid enzyme inhibitory properties of pomegranate fermented juice and seed oil flavonoids that pomegranate fermented juice and cold-pressed seed oil showed strong antioxidant activity, which was close to that of butylated hydroxyanisole and green tea and significantly greater than that of red wine. In fact, the flavonoids extracted from cold-pressed seed oil showed a 31 to 44% inhibition of sheep COX and a 69 to 81% inhibition of soybean lipoxygenase. Additionally, the flavonoids extracted from pomegranate fruit juice showed a 21 to 30% inhibition of soybean lipoxygenase, although no significant inhibition of sheep COX was observed.19 In addition, Adams et al. examined the effects of pomegranate juice extract on inflammatory cell signaling proteins in the HT-29 human colon cancer cell line. This study found that PFE significantly suppressed TNFa-induced COX-2 protein expression by 79%, total pomegranate tannin extract 55%, and punicalagin 48%.21 Thus, pomegranate extracts could be potential anti-inflammatory agents because of their COX-2 inhibitory activities.

6.6 EFFECT ON ANGIOGENESIS

It is now well recognized that the induction of the tumor vasculature or angiogenesis is critical for the progression of tumors. This tumor vascularization has been shown to be dependent on the chemokines (e.g., monocyte chemoattractant protein-1, inter-leukin [IL]-8) and growth factors (e.g., tumor necrosis factor, vascular endothelial growth factor) produced by macrophages, neutrophils, and other inflammatory cells.22 The production of these angiogenic factors has been shown to be regulated by NF-kB activation.23

Toi et al. evaluated the antiangiogenic potential of pomegranate seed oil or fermented juice polyphenols on angiogenic regulation by measuring the levels of vascular endothelial growth factor, IL-4, and migration inhibitory factor in the conditioned media of estrogen-sensitive (MCF-7) and estrogen-resistant (MDA-MB-231) human breast cancer cells and of immortalized normal human breast epithelial cells (MCF-10A).24 Their results showed a significant potential for down-regulation of angiogenesis by pomegranate fractions. Toi et al. also demonstrated an antipro-liferative effect on angiogenesis in human umbilical vein endothelial cells and in myometrial and amniotic fluid fibroblasts and an inhibition of tubule formation in human umbilical vein endothelial cells in an in vitro model that used glass carrier beads. The use of pomegranate fractions also led to a significant decrease in new blood vessel formation in a chicken chorioallantoic membrane model in vivo. These observations suggest that the antiangiogenic effects of pomegranate components are most likely mediated by the suppression of NF-kB.

6.7 EFFECT ON INVASION

When cancer treatment is ineffective, the remaining tumor cells inevitably infiltrate the surrounding normal tissue, which leads to tumor recurrence. Recent studies have shown that the ability of tumor cells to digest the extracellular matrix by secreting proteolytic enzymes correlates well with their degree of tissue invasiveness. For most primary human tumors, invasion is thought to be accomplished, at least in part, by proteases — namely, serine, cysteine, and metalloproteinases — that penetrate connective-tissue barriers, induce vascular remodeling, and destroy normal tissue. Several proteases, including matrix metalloproteinases and the serine protease uroki-nase-type plasminogen activator, that influence the invasive characteristics of tumors are regulated by NF-kB.25-27

Pomegranate extract has been shown to inhibit tumor invasion. In this regard, pomegranate hampered IL-ip-induced expression of matrix metalloproteinases by inhibiting the activation of mitogen-activated protein kinases and NF-kB in human chondrocytes in vitro.28 In another study, various components of pomegranate, including ellagic acid, caffeic acid, luteolin, and punicic acid, were tested as potential inhibitors of the in vitro invasion of human PC-3 prostate cancer cells across Matrigel artificial membranes. Although all compounds significantly inhibited invasion when administered individually, a supra-additive inhibition occurred when the components were administered together.29 Albrecht et al. similarly examined the effects of pomegranate oil and polyphenols and of pericarp polyphenols on human prostate cancer cell invasion across Matrigel in vitro. Again, all agents potently suppressed PC-3 invasion across Matrigel. Overall, these observations confirm the significant anti-invasive activity of pomegranate-derived materials against human prostate cancer.10

6.8 CONCLUSION

As previously stated, the medicinal use of pomegranate to treat various ailments has been well described in ancient texts and mythology. In more recent times, the scientific basis supporting this use has now become clear, with modern research providing an explanation of the numerous medicinal effects of the pomegranate. Specifically, the pomegranate and its various components have been shown to target a number of pathways that are responsible for various diseases, including cancers, and hence to be effective against many different disorders. In particular, pomegranate extracts have shown enough potential against tumors in numerous preclinical studies to warrant clinical trials.

Although modern drug design emphasizes the development of single agents with specific targets, the fact that whole pomegranate extract has been shown to be more efficacious than its individual components (a concept known as herbal synergy) suggests the limitations of this approach. Thus, the time to develop a dietary agent or drug that consists of a mixture of distinct molecules has come, however huge the challenge may be scientifically. Therefore, not only is an in-depth study to define the active agent(s) in PFE responsible for its antitumor effects warranted, additional clinical trials to further assess the chemopreventive and adjuvant therapeutic applications of the pomegranate in human cancers are also appropriate.

ACKNOWLEDGMENT

Supported by funds from the Clayton Foundation for Research (to BBA), a Department of Defense U.S. Army Breast Cancer Research Program grant (BC010610, to BBA), a P01 grant (CA-91844) on lung cancer chemoprevention from the National Institutes of Health (to BBA), a P50 Head and Neck Cancer SPORE grant from the National Institutes of Health (to BBA), and Cancer Center Core Grant CA-16672 (to BBA).

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17. Hora, J.J. et al., Chemopreventive effects of pomegranate seed oil on skin tumor development in CD1 mice, J. Med. Food, 6, 157, 2003.

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