Mechanisms Of Cancer Prevention Research Articles

Selenium and the prevention of prostate and colorectal cancer

Prostate and colorectal cancers are among the most common cancers and identifying modifiable risk factors are important steps to reduce the burden of these severe diseases. Results from several but mostly small observational studies as well as the secondary analysis of an intervention trial provide support for a chemopreventive effect of selenium on prostate and colorectal cancers. Results suggest effect modification by gender and smoking, but this interpretation is limited by the statistical power of previous studies. Several cancer preventive mechanisms have been described and it is likely that selenium acts through multiple pathways. In particular, the anti-oxidative and anti-inflammatory effects mediated through activity of selenoenzymes are discussed, given the relevance of oxidative stress and inflammation in these cancers. Genetic variation in selenoenzymes may modify the potential chemopreventive effect of selenium and need to be further investigated. Additional large observational studies using biomarkers of selenium intake and intervention trials, such as the Selenium and Vitamin E Cancer Prevention Trial, will be important to further evaluate the potential chemopreventive effect of selenium. Furthermore, characterization of functional effects of polymorphisms in selenoenzymes is needed.

Abstract B105: Inhibition of angiogenesis by oleanoleic acid-derived triterpenoids: mechanisms of action and potential prostate cancer prevention

Abstract B105 Angiogenesis is a limiting step for the switch from a dormant to malignant state in tumor progression. During tumor development tumor cells induce profound changes in the surrounding tissue, leading to the formation of an altered tumor microenvironment that is critical in permitting further tumor growth and tumor progression.. Angiogenesis and inflammation are common targets of many chemopreventive molecules that suppress the antiangiogenic switch in premalignant tumors.We evaluated in vitro and in vivo the antiangiogenic activity of two synthetic oleanoleic acid-derived triterpenoids under study for their chemopreventive and therapeutic potential, CDDO -Me and -Im. In vitro both compounds exhibited a strong inhibitory activity on endothelial cells isolated from umbilical veins (HUVEC). Futher, these compounds inhibited inflammatory cell chemotaxis towards specific chemokine stimului. The triterpenoids interfered with activation of the PI3K/Akt pathway following VEGF stimulation and activation of the NF-kappaB pathway subsequent to TNFalpha stimulation. Moreover CDDO-Me induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at very low concentrations, by acting agains GS3K pathway (Venè R, Larghero P, Arena G, Sporn MB, Albini A, Tosetti F. Cancer Res. 2008).In vivo CDDO-Im and especially CDDO-Me significantly inhibit neoangiogenesis in the matrigel sponge assay in C57BL mice, reducing both CD31+ cell number and Hb content in the sponges. We tested different schedules of treatment, by administering compounds as prevention before matrigel injection, as therapy after injection and as combination of prevention and therapy. All three protocols reduced angiogenesis when compared to controls the combinationof prevention and intervention was the most effective and at very low dosages. Since currently CDDO-Me is being assessed phase I trials in the US, the potential anti-angiogenic activity of these drugs should be taken into consideration in evaluating efficacy in these trials. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B105.

Prevention of chinese green tea on 3,4-benzopyrene-induced lung cancer and its mechanism in animal mode.

Chinese green tea is one of the daily consumption beverages in the world and is considered a promising cancer chemopreventive agent. In the present study, we investigate the role of lung cancer prevention by green tea and its mechanism. Three groups of female SD rats were kept with the same feed. Rats in group A were administrated with 1% green tea drinking, while in group B and group C with water only. Animals in group A and group B were given 3,4-benzopyrene-corn oil mixture pulmonary injection fortnightly for 4 times, while in group C corn oil only. Rats were sacrificed 1 year after the first injection under narcotism. Lung tumors and lung tissues were performed H&E staining for cancer identification. Each case of lung cancer was examined for expression of p53 and Bcl-2 with in situ hybridization analysis and immunohistochemistry staining. No cancer was found in rats in group C. However, in group B, 15 out of 20 rats were found generating lung cancer, and in group A, 6 out of 20 rats inducing lung cancer were recorded. The rate of lung carcinogenesis in rats was decreased from 75% to 30% by 1% chinese green tea oral administration (Chi-Square=8.12, P <0.01). Higher level of p53 expression in lung cancer tissues of group A was observed under microscope than that of group B, but the difference has no statistic significance (P >0.05). However, significantly lower level of Bcl-2 expression was found in lung cancer tissues of group A than that of group B (P <0.05). The results indicate that chinese green tea inhibits lung carcinogenesis. Chinese green tea can slightly upregulate expression of p53, but significantly downregulate expression of Bcl-2 in lung cancer, and this may be related to the mechanism of lung cancer prevention.

The Inhibition of Embryonic Histone Deacetylases as the Possible Mechanism Accounting for Axial Skeletal Malformations Induced by Sodium Salicylate

In spite of the large use of salicylates, introduced into clinical practice more than 100 years ago, their anti-inflammatory and cancer preventive mechanisms are still under study. Teratogenic effects of salicylates have been reported in experimental animals since 1959 but the pathogenic pathways and the mechanisms of action were never described until now. The aim of this work is to verify if the inhibition of embryonic histone deacetylase (HDAC) enzymes and the consequent tissue hyperacetylation could be the mechanism responsible for axial skeletal defects described after the exposure of pregnant rodents to sodium salicylate (SAL). E8 pregnant CD-1 mice were intraperitoneally treated with SAL 0-150-300-450 mg/kg and sacrificed at 1, 3, 5 h after treatment or at term of gestation (E18). E8 embryos were processed for Western blotting and immunostaining analyses, while skeletons of E18 fetuses were double stained for bone and cartilage. A group of control E8 embryos were used to prepare embryonic nuclear extract for the HDAC enzyme assay. A significant SAL dose-related HDAC inhibition activity, compatible with a mixed-type partial inhibition mechanism, was detected. A clear dose-related hyperacetylation of histones was observed in embryos exposed in utero to SAL, with a peak at 3 h after treatment of dams. The most hyperacetylated organs were somites and the heart. Histone hyperacetylation is suggested to be the mechanism accounting for SAL-related axial skeletal and cardiovascular defects and is proposed as the mechanism responsible for other biological effects of salicylates.

Oestrogen and the colon: potential mechanisms for cancer prevention

The role of oestrogen in oncogenesis has been examined extensively, especially in the context of breast cancer, and receptor modulators are an integral part of targeted treatment in this disease. The role of oestrogen signalling in colonic carcinoma is poorly understood. Men are more susceptible than women to colon cancer. Furthermore, hormone-replacement therapy affords an additive protective effect for postmenopausal women, and when these women do develop cancer, they typically have less aggressive disease. The discovery of a second oestrogen receptor (ERbeta) and its over expression in healthy human colon coupled with reduced expression in colon cancer suggests that this receptor might be involved. The underlying mechanism, however, remains largely unknown. In this Review, we discuss the various hypotheses presented in the published literature. We examine the cellular and molecular mechanisms through which oestrogen is purported to exert its protective influence, and we review the evidence available to support these claims.

Profiling of gene expression and proteomics in skin tissues of weight controlled mice via exercise and/or calorie restriction

Experimental evidence has demonstrated that weight control via dietary caloric restriction and/or exercise may prevent cancer. However, the underlying mechanisms are not clear. In this study, we randomly assigned SENCAR mice into 4 groups for 10 wks: ad libitum‐fed sedentary control, ad libitum‐fed exercise (AE), exercise but pair‐fed at the amount of control (PE), and 20% of dietary calorie restriction (DCR). Two hrs after topical TPA treatment, the skin tissues were analyzed by Affymetrix for gene expression and DIGE for proteomics, respectively. The body weights were significantly reduced in both DCR and PE but not AE mice when compared with the control. Among 39,000 transcripts, 1781, 1058, and 706 genes were found significantly changed by DCR, PE, and AE, respectively. PE and DCR showed similar impact on signaling pathways‐related gene expression as analyzed by GenMAPP. Braf in MAPK pathway and Akt1 in insulin signaling pathway appeared to be the key targets in response to weight change. Of the total 120 proteins identified, about 27 proteins were significantly changed by DCR. The correlation between gene and protein expression and their interaction to TPA‐induced cancer risk are further examined through Cytoscape and GenMAPP. Overview of all the gene and protein alterations may provide intrinsic mechanisms of cancer prevention by weight control (supported by NIH R01CA106397).

Chemopreventive effects of a selective cyclooxygenase-2 inhibitor (etodolac) on chemically induced intraductal papillary carcinoma of the pancreas in hamsters

The present study was designed to determine whether etodolac, a selective cyclooxygenase-2 inhibitor, prevents chemically induced intraductal papillary carcinoma (IPC) in the main pancreatic duct of hamsters. Hamsters were subjected to cholecystoduodenostomy with dissection of the distal end of the common duct. Four weeks after surgery, the surviving hamsters received subcutaneous injections of N-nitrosobis(2-oxopropyl)amine four times at a dose of 10 mg/kg body wt, every 2 weeks. The animals were divided into three groups according to the simultaneous oral intake of a standard pelleted diet containing etodolac at 0% (group CE, n = 30), 0.01% (group ET, n = 21) and 0.04% (group ET4, n = 25), respectively. Hamsters were killed for pathological examination at 36 weeks after the operation. The incidence of induced pancreatic carcinoma was 93, 81 and 72% in groups CE, ET and ET4, respectively. The pancreatic carcinomas were histologically classified into four types, i.e. tubular, papillary, cyst adenocarcinoma and IPC. The incidence of IPC and the number of IPCs per animal were significantly lower in groups ET4 (36% and 0.48) and ET (48% and 0.62) when compared with group CE (67% and 1.30). The proliferating cell nuclear antigen labeling indices in the non-cancerous epithelial cells of the main pancreatic duct were 2.8 and 6.8% in groups ET4 and ET, respectively, and were significantly lower than that in group CE (10.8%). In conclusion, etodolac inhibited N-nitrosobis(2-oxopropyl)amine-induced IPC in hamsters. Suppression of epithelial cell proliferation of the main pancreatic duct was considered as a possible mechanism of cancer prevention in this hamster model.

The 20th Aspen Cancer Conference: Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention, and Cancer Therapy 2005

The 20th Aspen Cancer Conference on Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention, and Cancer Therapy was held from July 24 to 28, 2005 in Aspen, Colorado. Recognizing the importance of a 20-year history of excellence, the 2005 Aspen Cancer Conference included an extended scientific program as well as several special presentations and events. The scientific program, developed by a Scientific Advisory Committee co-chaired by Benjamin F. Trump (AMC Cancer Center) and Curtis C. Harris (National Cancer Institute, NIH), featured an extra day of seminars by former Aspen Cancer Conference Keynote Speakers. The returning keynote speakers included J. Michael Bishop, Douglas Hanahan, Thea Tlsty, Tony Hunter, and Scott Lowe. In a special public Conference Session held at the Aspen Institute, former NIH director Harold Varmus lectured on Oncogenes and the Future of Cancer Therapy, Ms. Karen Allred presented a piano recital, and former Ambassador to the Netherlands K. Terry Dornbush described A Survivor’s Story, cancer from the perspective of a two-time prostate cancer survivor. Other special programming in acknowledgement of the 20th year of the Aspen Cancer Conference included a whole day devoted to drug discovery with presentations from Cecil Pickett (Schering-Plough Research Institute), James Doroshow (National Cancer Institute), and Carl Barrett (Novartis) a review of the history of the Aspen Cancer Conference in the context of the history of Aspen, Colorado presented by Donald King (National Library of Medicine), and an awards ceremony honoring sustained contribution to the Aspen Cancer Conference by Theodore Puck, Benjamin J. Trump, and Donald King. The goals of the Aspen Cancer Conference are: to understand the mechanisms of toxicity and carcinogenesis, to understand and minimize cancer risk, to assess the public-health impact of cancer risk, and to develop the scientific basis for improving the diagnosis, prevention, and treatment of toxic and neoplastic disease. The Aspen Cancer Conference fosters intense interaction, discussion, and collaboration among key stakeholders in cancer research. One of the strengths of the Conference is the sustained participation in and support of the Conference by leaders in cancer research from government, academic, and industry sectors. Because of its unusual qualities, the Aspen Cancer Conference provides an environment that is uniquely conducive to generating novel insights related to current issues in cancer prevention, intervention, and therapy. The 20th Aspen Cancer Conference included seven Conference Sessions, a Poster Session by Aspen Cancer Conference Fellows and numerous informal discussions. Session topics included Progress in Drug Development, Metastasis, Inflammation and Cancer, Stress and Cancer, Risk Assessment, Technology Innovations and Apoptosis. At the close of the 2005 Conference, the Scientific Advisory Committee met to select topics for the 21st Aspen Cancer Conference which will held from July 16 to 18, 2006. This meeting summary concisely describes the content of each of the Conference Sessions and the scientific portions of the Special Sessions.

The twenty‐second aspen cancer conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2007

The twenty‐second aspen cancer conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2007

Further insight into the impact of sodium selenite on selenoenzymes: High-dose selenite enhances hepatic thioredoxin reductase 1 activity as a consequence of liver injury

Selenium (Se) at supranutritional levels can enhance the activity of glutathione S-transferase (GST), whose gene is a target of nuclear factor erythroid-2 related factor 2 (Nrf2). Recent studies indicated that the thioredoxin reductase 1 (TrxR1) gene could also be targeted by Nrf2. Thus, high-dose Se may stimulate TrxR1 provided it enhances GST activity. Indeed, one study found that Se at supranutritional levels transiently increased hepatic TrxR1 activity. However, another study reported that supranutritional Se had no such effect on hepatic TrxR1 activity. In view of this discrepancy, the present research investigated whether high-dose Se has any impact on hepatic TrxR1. Moreover, we investigated whether Se preferentially activates GST over TrxR1. We observed that when sodium selenite (SS) caused liver injury, both hepatic TrxR1 activity and hepatic GST activity increased. Further experiments indicated that SS increased hepatic GST activity at either toxic or high but non-toxic dose levels; however, increase in hepatic TrxR1 activity occurred only at toxic levels, suggesting that enhanced TrxR1 activity correlates with liver injury. To corroborate this, we showed that hepatotoxic agents, thioacetamide or carbon tetrachloride, caused marked increases in hepatic TrxR1 activity. In conclusion, high-dose SS indeed can enhance hepatic TrxR1 activity, but only on the condition that it causes liver injury. High-dose SS affects hepatic GST more readily than hepatic TrxR1. Thus, the cancer-preventive mechanism of Se at non-toxic supranutritional levels relies more on its modulation of GST rather than TrxR1, at least in liver tissue.

Sites of Alkylation of Human Keap1 by Natural Chemoprevention Agents

Under basal conditions, the interaction of the cytosolic protein Keap1 (Kelch-like ECH-associated protein 1) with the transcription factor nuclear factor-E(2)-related factor 2 (Nrf2) results in a low level of expression of cytoprotective genes whose promoter region contains the antioxidant response element (ARE). Alkylation of one or more of the 27 cysteine sulfhydryl groups of human Keap1 is proposed to lead to Nrf2 nuclear accumulation, to upregulation of cytoprotective gene expression by the ARE, and to prevention of degenerative diseases, such as cancer. Therefore, identification of the most reactive of these cysteine residues toward specific electrophiles should help clarify this mechanism of cancer prevention, also known as chemoprevention. To address this issue, preliminary analyses of tryptic digests of Keap1 alkylated by the model electrophile 1-biotinamido-4-(4'-[maleimidoethyl-cyclohexane]-carboxamido) butane were carried out using liquid chromatographic-tandem mass spectrometry (LC-MS/MS) with a cylindrical ion trap mass spectrometer and also using LC-MS/MS with a hybrid linear ion trap FT ICR mass spectrometer. Because the FT ICR instrument provided more complete peptide sequencing coverage and enabled the identification of more alkylated cysteine residues, only this instrument was used in subsequent studies of Keap1 alkylation by three electrophilic natural products that can upregulate the ARE, xanthohumol, isoliquiritigenin, and 10-shogaol. Among the various cysteine residues of Keap1, C151 was most reactive toward these three electrophiles. These in vitro results agree with evidence from in vivo experiments, and indicate that C151 is the most important site of alkylation on Keap1 by chemoprevention agents that function by activating the ARE through Nrf2.

Cancer Prevention by Dietary Bioactive Components that Target the Immune Response

Dietary bioactive food components that interact with the immune response have considerable potential to reduce the risk of cancer. Reduction of chronic inflammation or its downstream consequences may represent a key mechanism that can be reduced through targeting signal transduction or through antioxidant effects. Major classes of macronutrients provide numerous examples, including amino acids such as glutamine or arginine, lipids such as the omega-3 polyunsaturated fatty acids, DHA or EPA, or novel carbohydrates such as various sources of beta-glucans. Vitamins such as C and E are commonly used as antioxidants, while zinc and selenium are minerals with a wide spectrum of impacts on the immune system. Some of the most potent immunomodulators are phytochemicals such as the polyphenols, EGCG or curcumin, or isothiocyanates such as PEITC. There is accumulating evidence for cancer prevention by probiotics and prebiotics, and these may also affect the immune response. Genomic approaches are becoming increasingly important in characterising potential mechanisms of cancer prevention, optimising the rational selection of dietary bioactive food components, or identifying humans with differing nutrient requirements for cancer protection.

Cancer Preventive Mechanismsof the Green Tea Polyphenol (-)-Epigallocatechin-3-gallate

Accumulating evidence indicates that consumption of tea, especially green tea, is good for preventing cancer. To elucidate the cancer preventive mechanisms of green tea, much effort has been devoted to investigating the anticancer effects of (-)-epigallocatechin-3-gallate (EGCG), the major component of green tea. It has been revealed that EGCG restrained carcinogenesis in a variety of tissues through inhibition of mitogen-activated protein kinases (MAPK), growth factor-related cell signaling, activation of activator protein 1 (AP-1) and nuclear factor-B (NF-kappaB), topoisomerase I, matrix metalloproteinases and other potential targets. Therefore, EGCG is a multipotent anticancer agent, which not only provides solid evidence to support the anticancer potential of green tea, but also offers new clues for discovering multiple-targeted anticancer drugs.

FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway

The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. Here, we report a novel component of this complex, termed FAAP100, which is essential for the stability of the core complex and directly interacts with FANCB and FANCL to form a stable subcomplex. Formation of this subcomplex protects each component from proteolytic degradation and also allows their coregulation by FANCA and FANCM during nuclear localization. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network.

Polyamine metabolism and cancer prevention

Colorectal cancer is one of a number of cancers that may be amenable to prevention. The NSAIDs (non-steroidal anti-inflammatory drugs) have been shown to be effective chemopreventative agents in humans, but their mechanism of action is not clear. The polyamines are cellular polycations that are essential for cell growth and are overproduced in cancer cells. It is our hypothesis that inhibition of polyamine metabolism is an integral part of the mechanism of cancer prevention mediated by NSAIDs.

Apoptotic cellular events for selenium compounds involved in cancer prevention

Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. Prior to occurrence of apoptosis, Se compounds alter the expression and/or activities of signaling molecules, mitochondria-associated factors, transcriptional factors, tumor suppressor genes, and cellular reduced glutathione. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess of selenoprotein synthesis can lead to DNA single-strand breaks. To elucidate the effects of Se on cytotoxic events, it should be remembered that the chemical forms and the dose of Se, and the experimental system used, are determinants of its biological activities. This mini-review focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic approach.

The twenty‐first Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2006

Molecular CarcinogenesisVolume 46, Issue 6 p. 415-435 Meeting Report The twenty-first Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, cancer prevention, and cancer therapy, 2006 Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland (Emeritus), Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MarylandLaboratory of Human Carcinogenesis, CCR, NCI, NIH, Room 3068, Building 37, 37 Convent Drive, Bethesda, MD 20892-4258.Search for more papers by this author Miriam Sander, Miriam Sander Page One Editorial Services, Boulder, ColoradoSearch for more papers by this authorBenjamin F. Trump, Benjamin F. Trump University of Maryland (Emeritus), Baltimore, MarylandSearch for more papers by this authorCurtis C. Harris, Corresponding Author Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MarylandLaboratory of Human Carcinogenesis, CCR, NCI, NIH, Room 3068, Building 37, 37 Convent Drive, Bethesda, MD 20892-4258.Search for more papers by this author First published: 21 December 2006 https://doi.org/10.1002/mc.20291Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume46, Issue6June 2007Pages 415-435 RelatedInformation

Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention and Cancer Therapy

Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention and Cancer Therapy

Mechanisms of Cancer Prevention by Green and Black Tea Polyphenols

Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kappaB as a result of decreased IkappaB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor an-tagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.

Flavonoids and Vitamin E Reduce the Release of the Angiogenic Peptide Vascular Endothelial Growth Factor from Human Tumor Cells

Neoangiogenesis is required for tumor development and progression. Many solid tumors induce vascular proliferation by production of angiogenic factors, prominently vascular endothelial growth factor (VEGF). Because nutrition is a causative factor for tumor prevention and promotion, we determined whether secondary plant constituents, i.e., flavonoids, tocopherols, curcumin, and other substances regulate VEGF in human tumor cells in vitro. VEGF release (concurrent with synthesis) from MDA human breast cancer cells and, for comparison, U-343 and U-118 glioma cells was measured by ELISA. Of 21 compounds tested, 9 showed significant inhibitory activity at 0.1 micromol/L in MDA human breast cancer cells. The rank order of inhibitory potency was naringin > rutin > alpha-tocopheryl succinate (alpha-TOS) > lovastatin > apigenin > genistein > alpha-tocopherol >or= kaempferol > gamma-tocopherol; chrysin and curcumin were inactive except at a concentration of 100 micromol/L. Glioma cells were similarly sensitive, with U343 more than U118, especially for alpha-TOS and tocopherols. Among the tocopherol derivatives, alpha-TOS (0.1 micromol/L) was the most effective in reducing VEGF release. Overall, the glycosylated flavonoids (i.e., naringin, a constituent of citrus fruits, and rutin, a constituent of cranberries) induced the greatest response to treatment at the lowest concentration in MDA human breast cancer cells. Inhibition of VEGF release by flavonoids, tocopherols, and lovastatin in these models of neoplastic cells suggests a novel mechanism for mammary cancer prevention.