Biomedical subjects

C Ip

Publications and source records attributed to C Ip.

133 records · Page 8Linked to original sources

PubMedDate not supplied

Chemoprevention with triphenylselenonium chloride in selenium-deficient rats.

Cancer chemoprevention by high levels of selenium, including compounds like sodium selenite or selenomethionine, is generally not accompanied by increases in known selenoenzymes. There has been no information on whether selenoenzymes are obligatory mediators of the anticarcinogenic effect of selenium. Our previous experience with triphenylselenonium chloride suggests that it might be an ideal agent for studying selenium chemoprevention while simultaneously precluding the synthesis of selenoenzymes. Triphenylselenonium chloride has excellent tumor inhibitory activity but does not support the repletion of selenoenzymes in animals that have been deprived of a bioavailable form of selenium. In the present experiments, we evaluated the efficacy of mammary cancer protection by this compound in rats fed either a selenite-deficient (< 0.01 ppm Se) or selenite-adequate (0.1 ppm Se) diet. We also measured the activities of liver glutathione peroxidase and thioredoxin reductase as markers of selenium bioavailability in these different treatment conditions. In carcinogen-treated control animals not receiving triphenylselenonium chloride, mammary tumor incidence and the total number of tumors were similar between the selenite-deficient and selenite-adequate groups. Thus the correction of selenium deficiency by the addition of 0.1 ppm Se as selenite did not have detectable anticarcinogenic effects. Supplementation of triphenylselenonium chloride at a level of 30 ppm Se suppressed mammary tumorigenesis by approximately 50% regardless of dietary selenium nutritional status. However, this supplement had little effect on tissue selenium levels and did not increase liver glutathione peroxidase or thioredoxin reductase activities. In contrast, a level of 0.1 ppm Se as selenite did not affect mammary tumorigenesis but markedly increased tissue selenium concentrations and selenoenzyme activities. It is concluded that triphenylselenonium chloride does not release inorganic selenium for selenoprotein synthesis and that its anticancer activity involves mechanisms that are probably intrinsic to the compound. This study also shows for the first time that selenium chemoprevention is possible in an environment of severely depressed selenoenzyme expression. Thus selenium chemoprevention efficacy can be separated experimentally from selenoprotein synthesis using this model system.

Animals↗

PubMedDate not supplied

Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland.

In the rat mammary carcinogenesis model, premalignant lesions known as intraductal proliferations (IDPs) are detectable within a few weeks after carcinogen treatment. These early transformed colonies are the precursors for the eventual formation of carcinomas. Our past research indicated that methylselenocysteine added to the diet of rats reduced the development of IDPs of all sizes (the size of each IDP was estimated operationally by the number of 5-micron serial sections showing the same pathology). The appearance of an IDP lesion represents a balance between cell proliferation and cell death. The modulation of these two cellular events by methylselenocysteine was investigated. The abdominal-inguinal mammary gland was excised 6 weeks after MNU administration. Proliferation and apoptosis were evaluated by BrdU labeling and the TUNEL assay, respectively. The expression levels of several cell cycle and apoptosis regulatory proteins, including cyclin D1, cyclin A, p27, p16, bcl-2, box and bak, were also assessed. All of the above endpoints were quantified by immunohistochemistry in paraffin-embedded sections. The results showed that the magnitude of the response to methylselenocysteine intervention seemed to depend on the size of the IDP lesion. For the purpose of this study, the small and large lesions were classified as those containing < or = 30 or > 30 serial sections, respectively. With the small lesions, methylselenocysteine significantly inhibited BrdU labeling and the expression of cyclin D1 and cyclin A, but increased the expression of p27. Interesting, only p27 was upregulated in the larger IDP lesions, while BrdU labeling and the cyclins were not affected. It is possible that the transformed phenotype becomes less sensitive to selenium-mediated arrest of proliferation once it progresses to a more advanced pathological stage. In contrast, methylselenocysteine stimulated apoptosis (TUNEL assay) by 3 to 4 fold, and this increase was evident in both the small and large IDP lesions. Consistent with the induction of apoptosis, a reduced expression of bcl-2 was also observed in the methylselenocysteine group. In summary, our data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis.

Animals↗

PubMedDate not supplied

Selenium compounds regulate p53 by common and distinctive mechanisms.

Selenium compounds show much promise in the prevention of prostate and other human cancers. Various selenium chemical forms have been shown to differ widely in their anticancer properties. The main dietary form is selenomethionine, which we showed modulated p53 activity by causing redox regulation of key p53 cysteine residues. In the current study we included other selenium chemical forms, sodium selenite and methyl-seleninic acid. All three forms are relevant selenium sources in human populations. All three forms can affect p53 activity defined as trans-activation of a p53-dependent reporter gene. In addition to the reduction of cysteine sulfhydryl groups, p53 phosphorylation was also affected in cells treated with selenium compounds. Methyl-seleninic acid caused phosphorylation of one or more p53 threonine residues, but did not affect any known serine phosphorylation sites. By contrast sodium selenite caused phosphorylation of p53 serines 20, 37 and 46 known to mediate apoptosis. Selenomethionine did not cause detectable phosphorylation of p53 serines or threonines. Our data show that, although p53 modulation may be a common denominator of selenium compounds, specific mechanisms of p53 activation differ among selenium chemical forms. Post-translational modifications of p53 are determinants of p53 activity and probably affect the threshold for p53-mediated functions. Different selenium chemical forms may differentially modify p53 for DNA repair or apoptosis in conjunction with a given level of endogenous or exogenous DNA damage.

Apoptosis↗

PubMedDate not supplied

Chemoprevention of mammary cancer by diallyl selenide, a novel organoselenium compound.

Previous research has demonstrated that structurally distinctive organoselenium compounds are superior to the corresponding sulfur analogs in cancer prevention. The present study was designed to extend this observation to diallyl selenide (DASe), a volatile synthetic compound, and diallyl sulfide (DAS), a flavor component of garlic. Their anticarcinogenic activities were evaluated using the 7,12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumor model. Rats were gavaged three times with DASe (6 or 12 mumol/kg body wt) or DAS (300, 900 or 1,800 mumol/kg) at 96, 48 and 24 hours before DMBA treatment. Significant tumor inhibition was found with the two doses of DASe and the highest dose of DAS. Based on these results, DASe appears to be at least 300 times more active than DAS. Analysis of total DMBA-DNA binding and individual DNA adducts in the mammary gland and liver showed that DASe had no effect on these parameters, suggesting that DASe might influence some unknown risk-associated events other than carcinogen activation/detoxification. Although the mechanism of action of DASe remains to be elucidated, its potential relevance to natural products will be discussed in the context of the chemistry of selenium-enriched garlic which has been reported to be effective in cancer protection in several studies.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Triphenylselenonium and diphenylselenide in cancer chemoprevention: comparative studies of anticarcinogenic efficacy, tissue selenium levels and excretion profile.

The objectives of the present study were to evaluate the cancer chemopreventive activity of triphenylselenonium chloride and diphenylselenide and to investigate the pharmacology of these two compounds with respect to their tissue accumulation and excretion profile. Although both phenyl selenide derivatives are related to each other structurally, they differ substantially in their intrinsic chemical properties. Triphenylselenonium is positively charged and amphiphilic, while diphenylselenide is uncharged and lipophilic. With the use of either the DMBA- or MNU-induced mammary tumor model in rats, triphenylselenonium was found to have superior chemopreventive efficacy compared to diphenylselenide. Both reagents were present at 30 ppm Se in the diet. At the time of sacrifice (22 weeks post-carcinogen), triphenylselenonium produced only minimal accumulation of selenium in the liver, kidney, mammary gland and plasma. In contrast, diphenylselenide caused a 2- to 3-fold elevation in selenium concentration depending on the tissue examined. Thus even though diphenylselenide was able to increase total selenium in tissues, it was less active in cancer protection. Fecal excretion following a single oral dose of triphenylselenonium (equal to the amount consumed in 1 day by an animal fed a diet containing 30 ppm Se) was approximately 78% and 8% of the dose during the first and second day, respectively, suggesting that the bulk of the dose was not absorbed. With diphenylselenide, fecal excretion was about 6% and 30% of the dose during the first and second day, and about 20% of the dose was excreted in the urine in each of the 2 days. This observation suggests that a large proportion of the diphenylselenide dose was absorbed and that urinary excretion was a major route of elimination for diphenylselenide once it was absorbed. Further studies are needed to clarify the basis for the differential effects of these phenyl selenide derivatives.

Animals↗

PubMedDate not supplied

Cytostasis and cancer chemoprevention: investigating the action of triphenylselenonium chloride in in vivo models of mammary carcinogenesis.

In this study, specific aspects of the cancer chemopreventive activity of triphenylselenonium chloride were investigated. The research was carried out in three in vivo models of MNU-induced mammary carcinogenesis in rats: a) a newly developed model characterized by the rapid but time-dependent appearance of intraductal proliferations, ductal carcinoma in situ and adenocarcinomas; b) a conventional model which took 5 months for full expression of all palpable tumors; and c) a late stage model which used tumor-bearing rats as the target population. Our work indicated that a) triphenylselenonium was able to delay the progression of premalignant to malignant lesions; b) chronic exposure to triphenylselenonium was required to sustain its cancer inhibitory activity; and c) triphenylselenonium failed to induce regression of established mammary carcinomas or suppress the emergence of new tumors when it was given at the late stage of carcinogenesis. These findings highlight the importance of understanding the range of activity of a given chemopreventive agent in order to maximize the probability of a successful outcome in the design of any future intervention trial.

Animals↗

PubMedDate not supplied

Activities of structurally-related lipophilic selenium compounds as cancer chemopreventive agents.

The present study compared the effects of four lipophilic forms of selenium with regard to cancer chemopreventive activity, tissue selenium accumulation, and bioavailability for synthesis of a selenoprotein. These reagents included methylphenyl selenide, diphenyl selenide, triphenyl-selenonium chloride, and p-xylylbis(methylselenide). The maximum tolerable dose (added in the diet) for each of these compounds was 5, 30, > 200, and 5 ppm Se, respectively. Because of differences in their tolerance, the cancer chemopreventive activities (in a methylnitrosourea-induced mammary tumor model in rats) of all 4 compounds were assessed at the 5 ppm Se level. Methylphenyl selenide was the most effective--79% inhibition, followed by p-xylylbis-(methylselenide)--66% inhibition, triphenylselenonium chloride--27% inhibition, and diphenyl selenide--10% inhibition. With respect to tissue selenium levels, p-xylylbis(methylselenide) produced the highest accumulation of selenium (approximately 3-fold increase in liver and kidney, 14-fold increase in mammary gland); methylphenyl selenide and diphenyl selenide showed more modest increases (1.5-fold or less in liver and kidney, 2.5-fold or less in mammary gland); while triphenylselenonium chloride resulted in no change. Highest bioavailability of selenium was observed for p-xylylbis(methylselenide), which was followed closely by methylphenyl selenide. Bioavailability was very low with diphenyl selenide, and undetectable with triphenylselenonium chloride. The chemical reactivities of these different selenium compounds are discussed in relation to the biological effects reported here.

Animals↗