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.

Dietary tomato inhibits angiogenesis in TRAMP prostate cancer but is not protective with a Western-style diet in this pilot study.

Prostate cancer (PCa) remains the second most diagnosed cancer worldwide. Higher body weight is associated with chronic inflammation, increased angiogenesis, and treatment-resistant tumor phenotypes. Dietary tomato reduces PCa risk, which may be due to tomato inhibition of angiogenesis and disruption of androgen signaling. This pilot study investigated the interplay between tomato powder (TP), incorporated into control (CON) and obesogenic (OB) diets, and PCa tumor growth and blood perfusion over time in a transgenic model of PCa (TRAMP). Ultrasound microvessel imaging (UMI) results showed good agreement with gold-standard immunohistochemistry quantification of endothelial cell density, indicating that this technique can be applied to non-invasively monitor tumor blood perfusion in vivo. Greater body weight was positively associated with tumor growth. We also found that TP significantly inhibited prostate tumor angiogenesis but that this inhibition differentially affected measured outcomes depending on CON or OB diets. TP led to reduced tumor growth, intratumoral inflammation, and intratumoral androgen-regulated gene expression (srd5a1, srd5a2) when incorporated with the CON diet but greater tumor growth and intratumoral gene expression when incorporated with the OB diet. Results from this study show that protective benefits from dietary tomato are lost, or may become deleterious, when combined with a Western-style diet.

Palmitoyl piperidinopiperidine, a novel derivative of 10­hydroxy­2­decenoic acid, as a potent and selective anticancer agent against human colon carcinoma cell lines.

The present study, to the best of our knowledge, is the first systematic study of the inhibitory effects of palmitoyl piperidinopiperidine (PPI; Japan Patent no. 5597427), on colon carcinogenesis. PPI exhibited marked growth inhibitory activity in several human colon carcinoma cell lines, with IC50 values of approximately 0.5­2.2 µM. In silico docking analysis indicated that PPI could bind to the SH2 domain of signal transducer and activator of transcription 3 (STAT3). PPI markedly inhibited the transcriptional activity of the SW837 cell line. Flowcytometric analysis demonstrated that PPI induced an increase in the number of cells in the G1 phase of the cell cycle, and induced sub­G1 fractions of cells at a higher concentration level of PPI. In the HT29 and SW837 cells, western blot analyses exhibited that in whole cell lysates, PPI induced a marked decrease in the expression levels of p­STAT3, but not in the levels of STAT3 in these cells. PPI also induced a marked decrease in the expression levels of both STAT3 and p­STAT3 in the chromatin fraction. In addition, PPI affected the protein expression levels of cyclin D1, p53, Bcl­2, Bcl­xL and vascular endothelial growth factor (VEGF). In the HT29 cells, PPI induced a marked and dose­dependent increase in the expression levels of Bax, cleaved caspase­3, cleaved caspase­7, cleaved caspase­8, cleaved caspase­9 and cleaved poly (ADP­ribose) polymerase (PARP). In animal model systems, PPI inhibited the growth of implanted carcinoma cells, and also induced a significant decrease in the multiplicity of colonic aberrant crypt foci. In addition, a marked and dose­dependent inhibition of angiogenesis of the chick chorioallantoic membrane was observed. As regards the possible molecular mechanisms, it is suggested that the inhibition of STAT3 by PPI may affect the function of molecules that are related to apoptosis, angiogenesis and cell cycle progression, eventually contributing to the PPI­induced growth inhibitory effects.

αVß3-Targeted Delivery of Camptothecin-Encapsulated Carbon Nanotube-Cyclic RGD in 2D and 3D Cancer Cell Culture.

Integrin αvß3 is widely expressed in various types of human cancer lines and plays a key role in angiogenesis for tumor growth and metastasis. Delivery of therapeutics to αvß3-expressing tumors can thus be a promising approach for treating cancer. For targeted delivery of anticancer therapeutics to αvß3-expressing tumor cells, cyclic arginylglycylaspartic acid (RGD) peptide was covalently conjugated to the surface of carboxylic acid-functionalized carbon nanotubes (fCNTs), and the topoisomerase I inhibitor camptothecin (CPT) was encapsulated in the fCNTs (CPT@fCNT-RGD). CPT@fCNT-RGD was successfully delivered to αvß3-expressing A375 cells, and compared with nontargeted CPT@fCNT, it provided 3.78- and 3.02-fold increases in the anticancer effect in 2D and 3D culture. Analysis of apoptosis-related gene expression shows that the expression levels of Bax, cleaved caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells were significantly increased in A375 cells incubated with CPT@fCNT-RGD compared with those incubated with CPT@fCNT. These results suggest that cyclic RGD-conjugated CNTs encapsulating an anticancer therapeutic can be a promising platform for treating cancer.

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.

The role of natural polyphenols in cell signaling and cytoprotection against cancer development.

The cytoprotective and anticancer action of dietary in-taken natural polyphenols has for long been attributed only to their direct radical scavenging activities. Currently it is well supported that those compounds display a broad spectrum of biological and pharmacological outcomes mediated by their complex metabolism, interaction with gut microbiota as well as direct interactions of their metabolites with key cellular signaling proteins. The beneficial effects of natural polyphenols and their synthetic derivatives are extensively studied in context of cancer prophylaxis and therapy. Herein we focus on cell signaling to explain the beneficial role of polyphenols at the three stages of cancer development: we review the recent proceedings about the impact of polyphenols on the cytoprotective antioxidant response and their proapoptotic action at the premalignant stage, and finally we present data showing how phenolic acids (e.g., caffeic, chlorogenic acids) and flavonols (e.g., quercetin) hamper the development of metastatic cancer.

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.

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer.

Freeze-dried black raspberries (BRB), their component anthocyanins (AC), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophageal cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. The present study determined the relation of changes in inflammatory markers to infiltration of innate immune cells into NMBA-treated esophagus. Rats were injected with NMBA (0.35 mg/kg) for 5 weeks while on control diet. Following NMBA treatment, rats were fed diets containing 6.1% BRB powder, an AC-rich fraction of BRBs (3.8 µmol/g), or 500 ppm PCA. At weeks 15, 25, and 35, inflammatory biomarker expression in the plasma and esophagus was quantified, and infiltration of immune cells in the esophagus was examined. At all three time points, BRB, AC, and PCA similarly affected cytokine production in the esophagus and plasma of NMBA-treated rats, relative to the NMBA-only control. These included decreased expression of the proinflammatory cytokine IL1ß and increased expression of the anti-inflammatory cytokine IL10. Moreover, all three diets also increased the expression of IL12, a cytokine that activates both cytolytic natural killer and CD8(+) T cells. In addition, the three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. Overall, our results suggest that another mechanism by which BRBs, ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis is by altering cytokine expression and innate immune cell trafficking into tumor tissues.

The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

BACKGROUND: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood. METHODS: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma. RESULTS: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4. CONCLUSIONS: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

Inhibition of Growth and Metastasis of Breast Cancer in Mice by Milk Fermented With Lactobacillus casei CRL 431.

Breast cancer is the second cause of death in women, who are especially related to uncontrolled metastasis. It was previously demonstrated that the administration of milk fermented by Lactobacillus casei CRL 431 [fermented milk (FM)] delayed the tumor growth in a murine breast cancer model. In this work we evaluated if the administration of FM to mice, starting when the tumor was measurable, can affect not only the tumor growth, but also the extravasation of tumor cells and the lung metastasis. The evaluation of immune cells-infiltrating tumors and lungs was also performed. Tumor volume was calculated. Whole blood, lungs, and liver were processed to count the number of colonies formed by tumor cells. Blood serum was obtained for monocyte chemoattractant protein-1, interleukin (IL)-10, and IL-6 determination, lung tissues for histologic observations, and tumor tissues for angiogenesis determination. Mice that received FM were compared with animals given milk or to the controls without any especial supplementation. The results showed that FM administration to mice decreased or suppressed tumor growth, with less tumor vascularity, extravasation of tumor cells, and lung metastasis. These benefits were associated to modulation of the immune response by decreasing the infiltration of macrophages in both the tumor and the lungs. FM administration maintained an increased antitumor response associated to CD8 lymphocytes, and also increased CD4 lymphocytes that can be involved in the modulation of the immune response. The future evaluation of cytokine profiles will allow knowing more about subpopulation of macrophages and lymphocytes associated to the beneficial effect of this probiotic in the breast cancer model.

Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide.

BACKGROUND: We previously reported that dietary glucosylceramides show cancer-prevention activity in a mouse xenograft model of human head and neck cancer cells (SCCKN). However, the mechanism was unclear. Ceramides, metabolites of glucosylceramides, induce apoptotic cell death in various malignancies. Here, we investigated the inhibitory effects of dietary glucosylceramides on tumor growth in vivo and in vitro. METHODS: SCCKN were subcutaneously inoculated into the right flanks of NOD/SCID mice. Mice were treated with or without dietary glucosylceramides (300 mg/kg) daily for 14 consecutive days after confirmation of tumor progression. Microvessel areas around the tumor were assessed by hematoxylin-eosin staining and immunohistochemistry of CD31, and, as markers for angiogenesis, protein levels of VEGF, VEGF receptor-2, and HIF-1α were assessed by Western blotting. Mass spectrometry was performed to measure the levels of sphingolipids in mouse serum after treatment with dietary glucosylceramides. RESULTS: Oral administration of glucosylceramides significantly decreased SCCKN growth in the xenograft model with inhibition of angioinvasion. In tumor-invasive areas, VEGF and HIF-1α in the tumor cells, and VEGF receptor-2 in endothelial cells decreased after treatment with dietary glucosylceramides. Dietary glucosylceramides increased serum levels of sphingosine-based ceramides as compared to the control. In SCCKN and UV♀2 cells, C6-ceramide suppressed the expressions of VEGF, VEGF receptor-2, and HIF-1α in vitro. CONCLUSION: These results suggest that dietary glucosylceramides trigger the de novo pathway of ceramide synthesis, indicating that sphingosine-based ceramide suppresses the growth of head and neck tumors through the inhibition of pro-angiogenic signals such as VEGF, VEGF receptor-2, and HIF-1α.

Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review.

As increased angiogenesis has been linked with the progression of ovarian cancer, a number of anti-angiogenic agents have been investigated, or are currently in development, as potential treatment options for patients with advanced disease. Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor, has gained European Medicines Agency approval for the front-line treatment of advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer in combination with carboplatin and paclitaxel, and for the treatment of first recurrence of platinum-sensitive ovarian cancer in combination with carboplatin and gemcitabine. We conducted a systematic literature review to identify available efficacy and safety data for bevacizumab in ovarian cancer as well as for newer anti-angiogenic agents in development. We analyzed published data from randomized, controlled phase II/III clinical trials enrolling women with ovarian cancer to receive treatment with bevacizumab. We also reviewed available data for emerging anti-angiogenic agents currently in phase II/III development, including trebananib, aflibercept, nintedanib, cediranib, imatinib, pazopanib, sorafenib and sunitinib. Significant efficacy gains were achieved with the addition of bevacizumab to standard chemotherapy in four randomized, double-blind, phase III trials, both as front-line treatment (GOG-0218 and ICON7) and in patients with recurrent disease (OCEANS and AURELIA). The type and frequency of bevacizumab-related adverse events was as expected in these studies based on published data. Promising efficacy data have been published for a number of emerging anti-angiogenic agents in phase III development for advanced ovarian cancer. Further research is needed to identify predictive or prognostic markers of response to bevacizumab in order to optimize patient selection and treatment benefit. Data from phase III trials of newer anti-angiogenic agents in ovarian cancer are awaited.

Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer.

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway.

Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration.

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth.

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.

Novel metals and metal complexes as platforms for cancer therapy.

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[Pt(II) (NH(3))(2)Cl(2)], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.

Conjugated Linoleic Acid (CLA) inhibits new vessel growth in the mammalian brain.

Conjugated Linoleic Acid (CLA) is fatty acid found endogenously in food sources that prevents new tumor development and reduces the growth of existing tumors in laboratory animals. CLA exerts its anti-carcinogenic effect by reducing VEGF and bFGF serum levels and by blocking flk-1 receptors, thereby inhibiting vascular growth critical to tumor growth and survival. Although the ability of CLA to inhibit angiogenesis in the peripheral nervous system is well characterized, it remains unknown whether CLA also affects vascular morphology in the central nervous system. Therefore, in the present study, exercising and sedentary animals received either standard rat chow or a specially formulated diet consisting of 0.5% CLA for 24 days. The brains were then examined to determine the extent of vascular growth in the cerebellum, a region known to exhibit robust exercise-induced angiogenesis. Our results indicate that CLA administration significantly reduces angiogenesis in the cerebellum. This study is the first to demonstrate the anti-angiogenic effect of CLA in the brain, and suggests that CLA be explored as a therapeutic treatment for cancer and tumors in the brain.

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.

Nutrient regulation of tumor and vascular endothelial cell proliferation.

Specific bioactive dietary components, such as the steroid receptor superfamily ligands vitamins A and D, have been studied extensively as potential cancer preventive and therapeutic agents due to their ability to regulate key processes in a variety of cell types which are dysregulated in neoplastic transformation namely, proliferation and differentiation. Alteration of one or more factors that regulate cell cycle control has been described as a predisposing event for early tumor development. In addition to tumor cell proliferation, the viability, growth and metastasis of solid tumors are also dependent on the vascularization of the tumor and establishment of blood flow. Both vitamins A and D exhibit anti-angiogenic properties which further strengthen their role as potential targets for the prevention and treatment of cancer. This review focuses on the role of vitamins A and D in preventing early tumor initiation and progression via control of the cell cycle in both tumor and vascular endothelial cells.