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 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemoprevention is prevention of cancer by administering natural or synthetic chemicals. Anti-androgens are among the promising chemopreventive agents for prostate cancer because prostate epithelium is androgen dependent. A National Cancer Institute supported large, randomized, clinical prostate cancer chemoprevention trial has been conducted to test the efficacy of finasteride, an inhibitor of 5-a-reductase, which converts testosterone to 5-hydroxy-testosterone. Now the focus is on micronutrients and phytochemicals, which have potential preventive effects against prostate cancer. Lycopene, soy isoflavones, vitamin E and selenium are among the most promising nutritional chemopreventive agents. Another NCI supported large clinical chemoprevention trial was recently started to investigate the efficacy of selenium and vitamin E, alone or in combination in the prevention of prostate cancer. Inclusion of appropriate biomarkers in clinical trials will help elucidate the mechanisms by which genetic and epigenetic pathways of carcinogenesis are modulated by nutrients and phytochemicals.
Cancer Metastasis Rev 2002
PMID:Chemoprevention of prostate cancer. 1246 50

The selection of micronutrients, defined as essential and nonessential dietary components consumed in minute quantities, for testing in clinical chemoprevention trials is based on the totality of evidence arising from epidemiologic, in vitro, animal, and clinical studies. Those micronutrients that surface with chemopreventive potential, in terms of high efficacy and low toxicity, in early-phase clinical studies are then candidates for large-scale, randomized clinical chemoprevention trials with cancer endpoints. Micronutrients currently being examined in National Cancer Institute (NCI)-sponsored phase I, II, or III chemoprevention trials for prostate, breast, and colon cancers include isoflavones, lycopene, selenized yeast, selenomethionine, selenium, vitamin E, perillyl alcohol, folic acid, vitamin D, calcium, and curcumin. The response to micronutrients may vary not only in magnitude but also in direction. This variation and response likely depend on individual genetic polymorphisms and/or interactions among dietary components that influence absorption, metabolism, or site of action. Research priorities include investigation of possible molecular targets for micronutrients and whether genetic and epigenetic events dictate direction and magnitude of the response.
Cancer Metastasis Rev 2002
PMID:Micronutrients in cancer chemoprevention. 1254 62

This article highlights some recent advances in selenium cancer chemoprevention research. It has been well documented that the chemical transformation of selenium to a monomethylated metabolite is an important step in achieving cancer prevention. Studies with the rat mammary carcinogenesis model suggested that methylselenocysteine (MSC), a good precursor for generating methylselenol endogenously, is able to block clonal expansion of premalignant lesions in the mammary gland. This finding supports the notion that selenium intervenes at an early stage of carcinogenesis. In addition to decreasing cell proliferation of the transformed colonies in vivo, MSC also enhances apoptosis. These same cellular responses are replicated with human premalignant breast cells grown in culture. cDNA microarray analysis indicated that selenium affects a multitude of molecular targets. Based on this information, a number of signaling pathways are proposed that could potentially provide insight into how selenium might block cell cycle progression and induce cell death.
Cancer Metastasis Rev 2002
PMID:New concepts in selenium chemoprevention. 1254 66

Lung cancer is the leading cause of cancer death in the United States. The current mainstays of lung cancer therapy are surgery, radiation and chemotherapy. These interventions have produced slight declines in mortality rates in the last 5 years however, it appears unlikely that marked improvements will occur in the near future. This grim overview argues strongly for new, emerging approaches for controlling this disease. Chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing or preventing carcinogenic progression to invasive cancer. Whether primary, secondary or tertiary settings, prevention has the highest potential to improve the dismal statistics associated with this cancer. Several randomized clinical or translational chemoprevention trials have been conducted. All have so far produced either neutral or harmful primary endpoint results showing that lung cancer was not prevented by alpha-tocopheral, beta-carotene, retinal, retinyl palmitate, N-acetylcysteine or isotretinoin in smokers. Secondary results supporting treatment with isotretinoin in 'never' and former smokers and data from prevention trials involving selenium and vitamin E however, are encouraging and offer a promising direction for future clinical study. Other areas of promise for future lung cancer chemoprevention study include the study of molecular markers of risk and drug activity, molecular targeting study, improved imaging techniques and new drug delivery systems.
Cancer Metastasis Rev 2002
PMID:Chemoprevention of lung cancer: current status and future prospects. 1254 71

Multiple intestinal neoplasia (Min) mice are a good model for investigating the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli effectively reduces colon cancer susceptibility. Although colon cancer cells mainly metastasize to the liver, little is known about the effects of selenium-enriched broccoli on gene expression in mouse liver. To better understand the protective role for selenium-enriched broccoli in tumorigenesis, a gene profile of the mouse liver was analyzed. Mice were fed either 0.11 mg selenium/kg control diet or 2.1 mg selenium/kg selenobroccoli diets for 10 weeks. Use of mouse pathway finder-1 GEArrays revealed that selenium-enriched broccoli moderately increased ikBalphakappaB, hsp86, gadd45 gene transcripts. In addition, analysis of the binding of liver nuclear proteins to (32)P-labeled probes demonstrated that selenium-enriched broccoli enhanced the binding of transcription factor p53, NFkappaB, AP-1 to their cis-acting elements. Collectively, these results suggest for the first time that selenium-enriched broccoli activates certain pro-apoptotic genes linked to p53, NFkappaB and stress signal pathways in response to "danger signals" such as tumorigenesis.
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PMID:Effect of selenium-enriched broccoli diet on differential gene expression in min mouse liver(1,2). 1277 Jun 47

The development of chemopreventive agents against prostate cancer would benefit from conclusive evidence of their efficacy in animal models that emulate human disease. To date there has been little in vivo evidence supporting their preventive capabilities. The 12T-10 Lady transgenic model spontaneously develops localized prostatic adenocarcinoma and neuroendocrine cancer followed by metastases, recapitulating the natural history of human prostate cancer in many respects. Using male Lady version of the transgenic adenocarcinoma of the mouse prostate mice, we show that administration of antioxidants (vitamin E, selenium, and lycopene) in the diet dramatically inhibits prostate cancer development and increases the disease free survival. Treatment of animals with the antioxidants resulted in a 4-fold reduction in the incidence of prostate cancer compared with the untreated animals. Prostate cancer developed in 73.68% (14 of 19) and 100% (19 of 19) of the animals from the standard and high fat diet, respectively. In contrast, only 10.53% (2 of 19) and 15.79% (3 of 19; P < 0.0001) of the animals in the standard and high fat diets supplemented with antioxidants developed tumors. The micronutrients were well tolerated with no evidence of antioxidant-related toxicity. Histopathological analysis confirmed absence of cancer in the additive treated groups. Immunohistochemistry demonstrated a strong correlation between disease-free state and increased levels of the prognostic marker p27(Kip1) and a marked decrease in proliferating cell nuclear antigen expression. These observations provide support for the chemopreventive effect of these micronutrients and some clues as to their mechanism of action.
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PMID:Antioxidants block prostate cancer in lady transgenic mice. 1531 34

Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
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PMID:PBISe, a novel selenium-containing drug for the treatment of malignant melanoma. 1848 17

Breast cancer frequently metastasizes to the skeleton resulting in bone degradation due to osteoclast activation. Metastases also downregulate differentiation and the bone-rebuilding function of osteoblasts. Moreover, cancer cells trigger osteoblast inflammatory stress responses. Pro-inflammatory mediators such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), expressed by osteoblasts (MC3T3-E1) stimulated with human breast cancer cell (MDA-MB-231) conditioned medium, are pivotal to osteoclast activation and metastasis. Given that these genes are regulated by nuclear factor-kappaB (NF-kappaB), a redox-sensitive transcription factor, we hypothesized that selenium (Se) could abrogate the inflammatory response to metastatic breast cancer cells by modulating NF-kappaB. Caffeic acid phenethyl ester and parthenolide inhibited NF-kappaB activation, as seen by gel shift assays and immunoblotting for p65 in nuclear fractions, as well as decreased production of IL-6 and MCP-1. Supplementation of MC3T3-E1 with methylseleninic acid (MSA) (0.5 microM to 4 microM) reduced the activation of NF-kappaB leading to a decrease in IL-6, MCP-1, COX-2 and iNOS in response to MDA-MB-231 conditioned medium. Addition of MSA to osteoblasts for as little as 15 min suppressed activation of NF-kappaB suggesting that short-lived active metabolites might be involved. However, brief exposure to MSA also brought about an increase in selenoprotein glutathione peroxidase 1. In summary, our data indicate that the osteoblast response to metastatic breast cancer cells is regulated by NF-kappaB activation, which can be effectively suppressed by MSA either through short-lived active metabolites and/or selenoproteins. Thus, Se supplementation may prevent the osteoblast inflammatory response or dampen the vicious cycle established when breast cancer cells, osteoblasts and osteoclasts interact.
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PMID:Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer. 1975 93

Selenium has cancer-preventive activity that is mediated, in part, through selenoproteins. The role of the 15-kDa selenoprotein (Sep15) in colon cancer was assessed by preparing and using mouse colon CT26 cells stably transfected with short hairpin RNA constructs targeting Sep15. Metabolic (75)Se labeling and Northern and Western blot analyses revealed that >90% of Sep15 was downregulated. Growth of the resulting Sep15-deficient CT26 cells was reduced (P < 0.01), and cells formed significantly (P < 0.001) fewer colonies in soft agar compared with control CT26 cells. Whereas most (14 of 15) BALB/c mice injected with control cells developed tumors, few (3 of 30) mice injected with Sep15-deficient cells developed tumors (P < 0.0001). The ability to form pulmonary metastases had similar results. Mice injected with the plasmid-transfected control cells had >250 lung metastases per mouse; however, mice injected with cells with downregulation of Sep15 only had 7.8 +/- 5.4 metastases. To investigate molecular targets affected by Sep15 status, gene expression patterns between control and knockdown CT26 cells were compared. Ingenuity Pathways Analysis was used to analyze the 1,045 genes that were significantly (P < 0.001) affected by Sep15 deficiency. The highest-scored biological functions were cancer and cellular growth and proliferation. Consistent with these observations, subsequent analyses revealed a G(2)-M cell cycle arrest in cells with targeted downregulation of Sep15. In contrast to CT26 cells, Sep15-targeted downregulation in Lewis lung carcinoma (LLC1) cells did not affect anchorage-dependent or anchorage-independent cell growth. These data suggest tissue specificity in the cancer-protective effects of Sep15 downregulation, which are mediated, at least in part, by influencing the cell cycle.
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PMID:Deficiency in the 15-kDa selenoprotein inhibits tumorigenicity and metastasis of colon cancer cells. 2038 23

This perspective discusses how well-conducted research by Penney et al. (beginning on page 604 in this issue of the journal) contributes to the incremental uncovering of the complex association between selenium and prostate cancer. These investigators' earlier findings and current questions, approaches, and findings regarding selenium for prostate cancer prevention are discussed. This group's work raises the following important inferences: Selenium may prevent poorer-prognosis prostate cancer and its progression to bony metastases and death, but only in men with genetic backgrounds that influence the requirement for selenium. These inferences point toward how to reconcile inconsistent prostate cancer risk results from the two randomized trials of selenium conducted to date.
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PMID:Is prostate cancer prevention with selenium all in the genes? 2042 30


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