Nutraceuticals and their role in tumor angiogenesis.

Angiogenesis plays a pivotal role in cancer initiation, maintenance, and progression. Diet may inhibit, retard or reverse these processes affecting angiogenesis (angioprevention). Nutraceuticals, such as omega-3 fatty acids, amino acids, proteins, vitamins, minerals, fibers, and phenolic compounds, improve health benefits as they are a source of bioactive compounds that, among other effects, can regulate angiogenesis. The literature concerning the pro-angiogenic and/or anti-angiogenic nutraceuticals and the possible activated pathways in cancer and other non-neoplastic diseases by in vivo and in vitro experiments are reviewed.

Inhibition of metastasis and angiogenesis in Hep-2 cells by wheatgrass extract - an in vitro and in silico approach.

Metastasis is the major hindrance in the treatment of all cancers, including laryngeal squamous cell carcinoma. Intensive researches are under way to identify the effective natural polyphenols with anti-metastatic ability for cancer treatment. Wheatgrass, an herbal plant has been reported to show anticancer effects. Hence, in this study, we aimed to analyze the anti-metastatic effect of methanol extract of wheatgrass (MEWG). The levels of metastatic marker proteins were determined by western blot. PI3K and AKT levels were determined by real time (RT)-PCR analysis. In silico molecular docking was done to check the interaction of the 14 components (identified by HPLC/GCMS) of MEWG with PI3K and AKT. MEWG effectively decreased the metastatic protein expressions, namely VEGF, MMP-9 and COX-2 and increased TIMP-2. RT-PCR results showed reduced m-RNA levels of both PI3K and AKT when compared to control. Molecular docking studies revealed interaction of most of the identified compounds of the extract with the important residues of PI3K and AKT. These findings indicate that MEWG inhibits metastasis and angiogenesis in Hep-2 cells possibly via PI3K/AKT due to the cumulative effect of polyphenols and other constituent present in extract. The compounds of the extract were also found to be directly involved in inhibition of AKT/PI3K, thus could help to restrain metastasis.

Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice.

Asthma is a chronic obstructive disease which is characterized by recurring airway inflammation, reversible airway obstruction, airway hyper responsiveness and vascular remodeling. Thymoquinone (TQ), an active ingredient isolated from Nigella sativa, was reported to exhibit anti-inflammation and anti-proliferation of in various cancer cells as well as epithelial cells. The aim of this study was to evaluate the effect of TQ on the inflammation, neoangiogenesis and vascular remodeling induced by Ovalbumin (OVA) in asthma mice in vivo and the anti-angiogenesis effects of TQ in VEGF-induced human umbilical vein endothelial cells (HUVECs) in vitro. Our results revealed that TQ inhibited the production of inflammatory factors interleukin-4/-5 (IL-4/-5) by enzyme-linked immunesorbent assay (ELISA). Immunohistochemistry analysis showed that the increase of platelet endothelial cell adhesion molecule-1, which is also known as CD31 and α-smooth muscle actinalpha (α-SMA) expression in asthma mice challenged by OVA was suppressed by TQ. Moreover, TQ suppressed the activation of VEGFR2-PI3K-Akt pathway and up-regulated the expression of Slit glycoprotein-2 (Slit-2) both in vivo and in vitro with the inhibition of tube information in HUVEC cells. Meanwhile immunofluorescence analysis showed that Slit-2 and Roundabout-4 (Robo-4) were co-expressing after TQ treatment in OVA-challenged asthma mice. Our study demonstrates that TQ attenuated the inflammatory reaction by antagonizing IL-4/-5 while the anti-neoangiogenesis effect of TQ is mediated by inhibition of vascular endothelial growth factor (VEGF) expression through VEGFR2/PI3K/Akt signaling pathway, which supports a potential role for TQ in ameliorating asthma.

Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy.

Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet containing 5% typical anhydrous milk fat (representing ~70% of the total dietary fat component) fed to Balb/c mice delayed the appearance of subcutaneous 4T1 breast and CT26 colon cancer tumours and inhibited their metastasis to the lung and liver, when compared to the control diet containing soybean oil as the only fat component. It augmented the inhibitory effects of paclitaxel on tumour growth and metastasis, and reduced the microvessel density of tumours. It displayed no apparent organ toxicity, but instead was beneficial for well-being of tumour-bearing mice by maintaining gastrocnemius muscle and epididymal adipose tissue that were otherwise depleted by cachexia. The milk fat diet ameliorated gut damage caused by paclitaxel in non-tumour-bearing mice, as evidenced by retention of jejunal morphology, villi length and intestinal γ-glutamyl transpeptidase activity, and inhibition of crypt apoptosis. It prevented loss of red and white blood cells due to both cancer-mediated immunosuppression and the cytotoxic effects of chemotherapy. The present study warrants the use of milk fat as an adjuvant to inhibit tumour metastasis during cancer chemotherapy, and to spare patients from the debilitating side-effects of cytotoxic drugs.

Short communication: PPAR gamma mediates a direct antiangiogenic effect of omega 3-PUFAs in proliferative retinopathy.

RATIONALE: Omega3 long-chain polyunsaturated fatty acids (omega3-PUFAs) are powerful modulators of angiogenesis. However, little is known about the mechanisms governing omega3-PUFA-dependent attenuation of angiogenesis. OBJECTIVE: This study aims to identify a major mechanism by which omega3-PUFAs attenuate retinal neovascularization. METHODS AND RESULTS: Administering omega3-PUFAs exclusively during the neovascular stage of the mouse model of oxygen-induced retinopathy induces a direct neovascularization reduction of more than 40% without altering vasoobliteration or the regrowth of normal vessels. Cotreatment with an inhibitor of peroxisome proliferator-activated receptor (PPAR)gamma almost completely abrogates this effect. Inhibition of PPARgamma also reverses the omega3-PUFA-induced reduction of retinal tumor necrosis factor-alpha, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial selectin, and angiopoietin 2 but not vascular endothelial growth factor. CONCLUSIONS: These results identify a direct, PPARgamma-mediated effect of omega3-PUFAs on retinal neovascularization formation and retinal angiogenic activation that is independent of vascular endothelial growth factor.

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides.

BACKGROUND: Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT). METHODS: Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume). RESULTS: The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 +/- 8.5 days versus only 23.3 +/- 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. CONCLUSION: Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further studies are needed to address the impact of this diet on other tumour-relevant functions such as invasive growth and metastasis.

Do the dietary supplements epigallocatechin gallate or vitamin e cause a radiomodifying response on tumors in vivo? A pilot study with murine breast carcinoma.

The primary aim of this study was to evaluate a systematic and reproducible assay to examine the potential radiomodifying effects of vitamin E (VE) or epigallocatechin gallate (EGCG), antioxidants commonly consumed by cancer patients as dietary supplements, on tumor control. C3H mice were randomized to a control diet or to the control diet supplemented with VE or EGCG. A tumor control dose 50% (TCD(50)) assay was used to evaluate for a radiomodifying response in stage IV murine cancer (MCa-IV) tumors, implanted in the hindleg of mice, and allowed to grow to 8 mm before receiving a single dose of radiation. The effects of VE and EGCG on intratumoral angiogenesis and apoptosis were evaluated in a group of nonirradiated mice using immunohistochemical staining. Cell proliferation assays were conducted on MCa-IV tumors in vitro. EGCG slowed tumor growth rate by 10%. EGCG and VE slowed tumor regrowth by 24 to 25%. There were no significant differences in TCD(50) values between the groups (control = 73.9 Gy, VE = 77.2 Gy, EGCG = 76.4 Gy); however, normal tissues were protected from late radiation effects (autoamputations) in the VE group. VE and EGCG increased tumor cell apoptosis and decreased tumor cell proliferation but had no effect on microvessel density. In this pilot study, neither VE nor EGCG exerted a significant radiomodifying effect on the MCa-IV tumor. Nonetheless, the suggestion of a small degree of tumor radioprotection by these antioxidant compounds warrants further research. As supplementation with VE radioprotected normal tissue, additional studies on this putative benefit are recommended.

Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids.

Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.