Tea polyphenols for the prevention of UVB-induced skin cancer.

Skin cancer is the most common type of cancer with increasing incidence rate and public health burden. Solar ultraviolet (UV) radiation causes an array of damaging cellular and molecular events that eventually lead to the development of skin cancer. Despite increased awareness about sun protection, the exposure rate remains high with less than 15% of men and 30% of women using sunscreen on a regular basis. Therefore, there is an imperative need for the development of novel preventive approaches. Skin cancer chemoprevention using phytochemicals either as dietary supplements or by topical applications has gained considerable attention due to their low toxicity, availability, and anticarcinogenic properties. Tea, the second most commonly consumed beverage in the world, is a rich source of promising phytochemicals known as polyphenols. In this review, we discuss the findings of various in vitro, in vivo and human studies signifying the chemopreventive effects of tea polyphenols against UVB-induced skin cancer. This is accomplished by exploring the role of tea polyphenols in DNA repair, inflammation, oxidative stress, signaling pathways, and epigenetics. Finally, this review discusses a variety of innovative delivery methods that enhance the photochemopreventive effects of tea polyphenols against skin cancer.

Pomegranate for Prevention and Treatment of Cancer: An Update.

Cancer is the second leading cause of death in the United States, and those who survive cancer may experience lasting difficulties, including treatment side effects, as well as physical, cognitive, and psychosocial struggles. Naturally-occurring agents from dietary fruits and vegetables have received considerable attention for the prevention and treatment of cancers. These natural agents are safe and cost efficient in contrast to expensive chemotherapeutic agents, which may induce significant side effects. The pomegranate (Punica granatum L.) fruit has been used for the prevention and treatment of a multitude of diseases and ailments for centuries in ancient cultures. Pomegranate exhibits strong antioxidant activity and is a rich source of anthocyanins, ellagitannins, and hydrolysable tannins. Studies have shown that the pomegranate fruit as well as its juice, extract, and oil exert anti-inflammatory, anti-proliferative, and anti-tumorigenic properties by modulating multiple signaling pathways, which suggest its use as a promising chemopreventive/chemotherapeutic agent. This review summarizes preclinical and clinical studies highlighting the role of pomegranate in prevention and treatment of skin, breast, prostate, lung, and colon cancers.

Fisetin and Its Role in Chronic Diseases.

Chronic inflammation is a prolonged and dysregulated immune response leading to a wide variety of physiological and pathological conditions such as neurological abnormalities, cardiovascular diseases, diabetes, obesity, pulmonary diseases, immunological diseases, cancers, and other life-threatening conditions. Therefore, inhibition of persistent inflammation will reduce the risk of inflammation-associated chronic diseases. Inflammation-related chronic diseases require chronic treatment without side effects. Use of traditional medicines and restricted diet has been utilized by mankind for ages to prevent or treat several chronic diseases. Bioactive dietary agents or "Nutraceuticals" present in several fruits, vegetables, legumes, cereals, fibers, and certain spices have shown potential to inhibit or reverse the inflammatory responses and several chronic diseases related to chronic inflammation. Due to safe, nontoxic, and preventive benefits, the use of nutraceuticals as dietary supplements or functional foods has increased in the Western world. Fisetin (3,3',4',7-tetrahydroxyflavone) is a dietary flavonoid found in various fruits (strawberries, apples, mangoes, persimmons, kiwis, and grapes), vegetables (tomatoes, onions, and cucumbers), nuts, and wine that has shown strong anti-inflammatory, anti-oxidant, anti-tumorigenic, anti-invasive, anti-angiogenic, anti-diabetic, neuroprotective, and cardioprotective effects in cell culture and in animal models relevant to human diseases. In this chapter, we discuss the beneficial pharmacological effects of fisetin against different pathological conditions with special emphasis on diseases related to chronic inflammatory conditions.

Phytochemicals for the Management of Melanoma.

Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.

Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin.T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.

Pomegranate fruit extract inhibits UVB-induced inflammation and proliferation by modulating NF-κB and MAPK signaling pathways in mouse skin.

There is considerable interest in the identification of natural agents capable of affording protection to skin from the adverse effects of solar ultraviolet B (UVB) radiation. Pomegranate (Punica granatum L.) fruit possesses as strong antioxidant, anti-inflammatory and antiproliferative properties. Recently, we have shown that oral feeding of pomegranate fruit extract (PFE) to mice afforded substantial protection from the adverse effects of single UVB radiation via modulation in early biomarkers of photocarcinogenesis. This study was designed to investigate the photochemopreventive effects of PFE (0.2%, wt/vol) after multiple UVB irradiations (180 mJ cm(-2), on alternative day, for a total of seven treatments) to the skin of SKH-1 hairless mice. Oral feeding of PFE to SKH-1 mice inhibited UVB-induced epidermal hyperplasia, infiltration of leukocytes, protein oxidation and lipid peroxidation. Immunoblot analysis demonstrated that oral feeding of PFE to mice inhibited UVB-induced (1) nuclear translocation and phosphorylation of nuclear factor kappa B/p65, (2) phosphorylation and degradation of IκBα, (3) activation of IKKα/ΙΚΚß and (4) phosphorylation of mitogen-activated protein kinase proteins and c-Jun. PFE consumption also inhibited UVB-induced protein expression of (1) COX-2 and iNOS, (2) PCNA and cyclin D1 and (3) matrix metalloproteinases-2,-3 and -9 in mouse skin. Taken together, these data show that PFE consumption afforded protection to mouse skin against the adverse effects of UVB radiation by modulating UVB-induced signaling pathways.

Oral feeding of pomegranate fruit extract inhibits early biomarkers of UVB radiation-induced carcinogenesis in SKH-1 hairless mouse epidermis.

Pomegranate from the plant Punica granatum L. possesses strong antioxidant and anti-inflammatory properties. Recently, we have demonstrated that treatment of normal human epidermal keratinocytes with pomegranate fruit extract (PFE) inhibited UVB-mediated activation of nuclear factor kappa B (NF-κB) and mitogen activated protein kinases pathways. Here, we evaluated the effect of PFE on early biomarkers of photocarcinogenesis employing SKH-1 hairless mice. PFE was provided in drinking water (0.2%, wt/vol) to SKH-1 hairless mice for 14 days before a single UVB (180 mJ cm(-2)) irradiation. We found that oral feeding of PFE inhibited UVB-induced: (1) skin edema; (2) hyperplasia; (3) infiltration of leukocytes; (4) lipid peroxidation; (5) hydrogen peroxide generation; (6) ornithine decarboxylase (ODC) activity; and (7) ODC, cyclooxygenase-2 and proliferating cell nuclear antigen protein expression. Oral feeding of PFE enhanced repair of UVB-mediated formation of cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Importantly, PFE treatment further enhanced UVB-mediated increase in tumor suppressor p53 and cyclin kinase inhibitor p21. Furthermore, oral feeding of PFE inhibited UVB-mediated: (1) nuclear translocation of NF-κB; (2) activation of IKKα; and (3) phosphorylation and degradation of IκBα. Taken together, we provide evidence that oral feeding of PFE to mice affords substantial protection from the adverse effects of UVB radiation via modulation in early biomarkers of photocarcinogenesis and provide suggestion for its photochemopreventive potential.

In vitro and in vivo effects of water extract of white cocoa tea (Camellia ptilophylla) against human prostate cancer.

PURPOSE: We evaluated the chemotherapeutic effect of water extract of white cocoa tea (WCTE) against human prostate cancer (PCa) in vitro and in vivo. METHODS: Cell viability and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Western blotting was performed to determine changes in levels of various proteins. Effect of WCTE was determined in athymic nude mice implanted with PC-3 cells. RESULTS: Treatment with WCTE (100-150 microg/ml) inhibited cell proliferation, which correlated with G2/M phase arrest in PC-3 cells. WCTE treatment to PC-3 cells resulted in (1) induction of WAF1/p21 and KIP1/p27, (2) decrease in cyclins D1, D2 and E, (3) decrease in cyclin-dependent kinase (cdk) 2, 4 and 6, (4) induction of Bax and down-regulation of Bcl-2, (5) decrease in procaspase-3, -8, (6) inhibition of nuclear translocation and phosphorylation of NF-kappaB and activation of IKKalpha, and (7) inhibition of phosphorylation and degradation of IkappaBalpha. Oral administration of WCTE (0.1 and 0.2%, wt/vol) to athymic nude mice resulted in greater than 50% inhibition of tumor growth. There was a decrease in expressions of cyclin D1, Bcl-2 and p-NF-kappaB and an increase in WAF1/p21 and Bax in tumor tissues of mice. CONCLUSION: WCTE can be a useful chemotherapeutic agent against human PCa.

Protective effect of pomegranate-derived products on UVB-mediated damage in human reconstituted skin.

Solar ultraviolet (UV) radiation, particularly its UVB (290-320 nm) component, is the primary cause of many adverse biological effects including photoageing and skin cancer. UVB radiation causes DNA damage, protein oxidation and induces matrix metalloproteinases (MMPs). Photochemoprevention via the use of botanical antioxidants in affording protection to human skin against UVB damage is receiving increasing attention. Pomegranate, from the tree Punica granatum, contains anthocyanins and hydrolysable tannins and possesses strong antioxidant and anti-tumor-promoting properties. In this study, we determined the effect of pomegranate-derived products--POMx juice, POMx extract and pomegranate oil (POMo)--against UVB-mediated damage using reconstituted human skin (EpiDerm(TM) FT-200). EpiDerm was treated with POMx juice (1-2 microl/0.1 ml/well), POMx extract (5-10 microg/0.1 ml/well) and POMo (1-2 microl/0.1 ml/well) for 1 h prior to UVB (60 mJ/cm(2)) irradiation and was harvested 12 h post-UVB to assess protein oxidation, markers of DNA damage and photoageing by Western blot analysis and immunohistochemistry. Pretreatment of Epiderm with pomegranate-derived products resulted in inhibition of UVB-induced (i) cyclobutane pyrimidine dimers (CPD), (ii) 8-dihydro-2'-deoxyguanosine (8-OHdG), (iii) protein oxidation and (iv) proliferating cell nuclear antigen (PCNA) protein expression. We also found that pretreatment of Epiderm with pomegranate-derived products resulted in inhibition of UVB-induced (i) collagenase (MMP-1), (ii) gelatinase (MMP-2, MMP-9), (iii) stromelysin (MMP-3), (iv) marilysin (MMP-7), (v) elastase (MMP-12) and (vi) tropoelastin. Gelatin zymography revealed that pomegranate-derived products inhibited UVB-induced MMP-2 and MMP-9 activities. Pomegranate-derived products also caused a decrease in UVB-induced protein expression of c-Fos and phosphorylation of c-Jun. Collectively, these results suggest that all three pomegranate-derived products may be useful against UVB-induced damage to human skin.

A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways.

Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30-120 microM) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of beta-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-kappaB). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-kappaB-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer.

Guggulsterone modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in SENCAR mice.

Guggulsterone (GUG), a resin of the Commiphora mukul tree, has been used in ayurvedic medicine for centuries to treat a variety of ailments. Recent studies have suggested that GUG may also possess anticancer effects. In the present study, we show that GUG possesses antitumor-promoting effects in SENCAR mouse skin tumorigenesis model. We first determined the effect of topical application of GUG to mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of GUG (1.6 micromol per mouse) 30 min prior to TPA (3.2 nmol per mouse) application onto the skin of mice afforded significant inhibition against TPA-mediated increase in skin edema and hyperplasia. Topical application of GUG was also found to result in substantial inhibition against TPA-induced epidermal (i) ornithine decarboxylase (ODC) activity; (ii) ODC, cyclooxygenase-2 and inducible nitric oxide synthase protein expressions; (iii) phosphorylation of extracellular signal-regulated kinase 1/2, c-jun N-terminal kinases and p38; (iv) activation of NF-kappaB/p65 and IKK alpha/beta and (v) phosphorylation and degradation of I kappaB alpha. We next assessed the effect of topically applied GUG on TPA-induced skin tumor promotion in 7,12-dimethyl benz[a]anthracene-initiated mice. Compared with non-GUG-pretreated mice, animals pretreated with GUG showed significantly reduced tumor incidence, lower tumor body burden and a significant delay in the latency period for tumor appearance from 5 to 11 weeks. These results provide the first evidence that GUG possesses anti-skin tumor-promoting effects in SENCAR mice and inhibits conventional as well as novel biomarkers of tumor promotion. In summary, GUG could be useful for delaying tumor growth in humans.

Dietary agents for chemoprevention of prostate cancer.

Prostate cancer (CaP) is the leading cause of cancer-related deaths in American men, responsible for over 29,000 deaths in the year 2007. Chemoprevention is a plausible and cost-effective approach to reduce cancer morbidity and mortality through inhibition of precancerous events before the occurrence of clinical disease. Indeed, CaP is an ideal candidate disease for chemopreventive intervention as it is typically diagnosed in the elderly population with a relatively slower rate of growth and progression. The potential of dietary substances to act as chemopreventive agents against CaP is increasingly appreciated. Further, epidemiological studies have identified significant correlations between CaP incidence and dietary habits. It is hoped that, combining the knowledge based on agents with targets, we will be able to build an armamentarium of naturally occurring chemopreventive substances that could prevent or slow down the development and progression of CaP. In this review, we have summarized the findings from clinical and preclinical studies on dietary agents including green tea, pomegranate, lupeol, fisetin, and delphinidin that are currently being investigated in our laboratory for their chemopreventive potential against CaP.

Phytochemicals for prevention of solar ultraviolet radiation-induced damages.

While solar light is indispensable for sustenance of life, excessive exposure can cause several skin-related disorders. The UV part of solar radiation, in particular, is linked to disorders ranging from mild inflammatory effects of the skin to as serious as causing several different types of cancers. Changes in lifestyle together with depletion in the atmospheric ozone layer during the last few decades have led to an increase in the incidence of skin cancer. Skin cancers consisting of basal and squamous cell carcinomas are especially linked to the UVB part of solar radiation. Reducing excessive exposure to solar radiation is desirable; however, as this approach is unavoidable, it is suggested that other novel strategies be developed to reduce the effects of solar radiation to skin. One approach to reduce the harmful effects of solar radiation is through the use of phytochemicals, an approach that is popularly known as "Photochemoprotection." In recent years many phytochemicals with potential antioxidant properties have been identified and found to be photoprotective in nature. We describe here some of the most popular phytochemicals being studied that have the potential to reduce the harmful effects associated with solar UV radiation.

Prevention of prostate cancer through custom tailoring of chemopreventive regimen.

One practical way to control cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention naturally occurring diet-based agents are preferred over synthetic agents. For a long time, the prevailing mantra of cancer chemoprevention has been: "Find effective agents with acceptable or no toxicity and use them in preventing cancer in relatively healthy people or individuals at high risk for developing cancer". In pursuing this goal many naturally occurring phytochemicals capable of affording protection against carcinogenesis in preclinical settings in experimental animals have been described. However, clinical trials of single agents have yielded disappointing results. Since carcinogenesis is a multistage phenomenon in which many normal cellular pathways become aberrant, it is unlikely that one agent could prove effective in preventing cancer. This review underscores the need to build an armamentarium of naturally occurring chemopreventive substances that could prevent or slow down the development and progression of prostate cancer. Thus, the new effective approach for cancer prevention "building a customized mechanism-based chemoprevention cocktail of naturally occurring substances" is advocated.

Cancer chemoprevention through dietary antioxidants: progress and promise.

It is estimated that nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification. Various dietary antioxidants have shown considerable promise as effective agents for cancer prevention by reducing oxidative stress which has been implicated in the development of many diseases, including cancer. Therefore, for reducing the incidence of cancer, modifications in dietary habits, especially by increasing consumption of fruits and vegetables rich in antioxidants, are increasingly advocated. Accumulating research evidence suggests that many dietary factors may be used alone or in combination with traditional chemotherapeutic agents to prevent the occurrence of cancer, their metastatic spread, or even to treat cancer. The reduced cancer risk and lack of toxicity associated with high intake of fruits and vegetables suggest that specific concentrations of antioxidant agents from these dietary sources may produce cancer chemopreventive effects without causing significant levels of toxicity. This review presents an extensive analysis of the key findings from studies on the effects of dietary antioxidants such as tea polyphenols, curcumin, genistein, resveratrol, lycopene, pomegranate, and lupeol against cancers of the skin, prostate, breast, lung, and liver. This research is also leading to the identification of novel cancer drug targets.

Chemoprevention of prostate cancer through dietary agents: progress and promise.

Prostate cancer (CaP) is second only to lung cancer as the cause of cancer-related deaths in American men and is responsible for over 29,000 deaths per year. One promising approach to reduce the incidence of CaP is through chemoprevention, which has been recognized as a plausible and cost-effective approach to reduce cancer morbidity and mortality by inhibiting precancerous events before the occurrence of clinical disease. Indeed, CaP is an ideal candidate disease for chemoprevention because it is typically diagnosed in the elderly population with a relatively slower rate of growth and progression, and therefore, even a modest delay in the development of cancer, achieved through pharmacologic or nutritional intervention, could result in substantial reduction in the incidence of clinically detectable disease. In this review, we have summarized the recent investigations and mechanistic studies on CaP chemoprevention using dietary agents, such as selenium, vitamins D and E, lycopene, phytoestrogens, flavonoids, and green tea polyphenols. Well-designed trials are required to delineate the potential clinical usefulness of these agents through issues, such as determining the optimal period and route of administration, systemic bioavailability, optimal dosing and toxicity of the agent, and single or combinatorial approach. It is hoped that, combining the knowledge based on agents with targets, effective approaches for CaP chemoprevention can be established.

Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo.

PURPOSE: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (-)epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. EXPERIMENTAL DESIGN: Human prostate cancer cells LNCaP, PC-3, and CWR22Rnu1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. RESULTS: Combination of EGCG (10-40 micromol/L) and NS-398 (10 micromol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor gamma; and (e) inhibition of nuclear factor-kappaB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. CONCLUSIONS: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.

Oral consumption of pomegranate fruit extract inhibits growth and progression of primary lung tumors in mice.

To develop novel mechanism-based preventive approaches for lung cancer, we examined the effect of oral consumption of a human achievable dose of pomegranate fruit extract (PFE) on growth, progression, angiogenesis, and signaling pathways in two mouse lung tumor protocols. Benzo(a)pyrene [B(a)P] and N-nitroso-tris-chloroethylurea (NTCU) were used to induce lung tumors, and PFE was given in drinking water to A/J mice. Lung tumor yield was examined on the 84th day and 140 days after B(a)P dosing and 240 days after NTCU treatment. Mice treated with PFE and exposed to B(a)P and NTCU had statistically significant lower lung tumor multiplicities than mice treated with carcinogens only. Tumor reduction was 53.9% and 61.6% in the B(a)P + PFE group at 84 and 140 days, respectively, compared with the B(a)P group. The NTCU + PFE group had 65.9% tumor reduction compared with the NTCU group at 240 days. Immunoblot analysis and immunohistochemistry were used to determine effect on cell survival pathways and markers of cellular proliferation and angiogenesis. PFE treatment caused inhibition of (a) activation of nuclear factor-kappaB and IkappaBalpha kinase, (b) degradation and phosphorylation of IkappaBalpha, (c) phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase 1/2, and p38), (d) phosphatidylinositol 3-kinase (p85 and p110), (e) phosphorylation of Akt at Thr(308), (f) activation of mammalian target of rapamycin signaling, (g) phosphorylation of c-met, and (h) markers of cell proliferation (Ki-67 and proliferating cell nuclear antigen) and angiogenesis (inducible nitric oxide synthase, CD31, and vascular endothelial growth factor) in lungs of B(a)P- and NTCU-treated mice. Thus, our data show that PFE significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer.

Pomegranate fruit extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor growth in athymic nude mice.

Developing novel mechanism-based chemopreventive approaches for lung cancer through the use of dietary substances which humans can accept has become an important goal. In the present study, employing normal human bronchial epithelial cells (NHBE) and human lung carcinoma A549 cells, we first compared the growth inhibitory effects of pomegranate fruit extract (PFE). Treatment of PFE (50-150 microg/ml) for 72 h was found to result in a decrease in the viability of A549 cells but had only minimal effects on NHBE cells as assessed by the MTT and Trypan blue assays. PFE treatment of A549 cells also resulted in dose-dependent arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis). We further found that PFE treatment also resulted in (i) induction of WAF1/p21 and KIP1/p27, (ii) decrease in the protein expressions of cyclins D1, D2 and E, and (iii) decrease in cyclin-dependent kinase (cdk) 2, cdk4 and cdk6 expression. The treatment of cells with PFE inhibited (i) phosphorylation of MAPK proteins, (ii) inhibition of PI3K, (iii) phosphorylation of Akt at Thr308, (iv) NF-kappaB and IKKalpha, (v) degradation and phosphorylation of IkappaBalpha, and (vi) Ki-67 and PCNA. We also found that PFE treatment to A549 cells resulted in inhibition of NF-kappaB DNA-binding activity. Oral administration of PFE (0.1 and 0.2%, wt/vol) to athymic nude mice implanted with A549 cells resulted in a significant inhibition in tumor growth. Our results provide a suggestion that PFE can be a useful chemopreventive/chemotherapeutic agent against human lung cancer.

Botanical antioxidants in the prevention of photocarcinogenesis and photoaging.

Exposure of the skin to ultraviolet (UV) radiation, particularly its UV-B component (280-320 nm), from the sun results in erythema, edema, hyperplasia, hyperpigmentation, sunburn cells, immunosuppression, photoaging, and skin cancer. Amongst these various adverse effects of UV-B radiation, skin cancer and photoaging are of great concern. More recent changes in lifestyle have led to a significant increase in the amount of UV-B radiation people receive leading to a surge in the incidence of skin cancer and photoaging. As these trends are likely to continue in the foreseeable future, the adverse effect of UV-B has become a major human health concern. Therefore, development of novel strategies to reduce the occurrence of skin cancer and delay the process of photoaging are highly desirable goals. One approach to reduce their occurrence is through photochemoprevention, which we define as the use of agents capable of ameliorating the adverse effects of UV-B on the skin. Photochemoprevention via use of botanical antioxidants, present in the common diet of human have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. This review will focus on the effects of selected botanical antioxidants in the prevention of photocarcinogenesis and photoaging.