Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor induction with chronic feeding of methyl-donor-deficient diets has been well established; however, the biochemical and molecular mechanisms which predipose to tumorigenesis in this model are still not well understood. The purpose of the present investigation was to assess DNA damage and altered nucleotide metabolism in lymphocytes from Fischer 344 rats fed one of four semi-purified diets: (i) deficient in methionine and choline; (ii) deficient in folic acid; (iii) deficient in methionine, choline and folic acid; or (iv) a supplemented control diet. The accumulation of DNA-strand breaks, as assessed by DNA unwinding in alkali, was increased in lymphocytes from both the methionine/choline-deficient and folate-deficient groups, but was most severe in the group deficient in all three methyl donors. Lymphocyte DNA damage was consistently associated with alterations in folate-dependent thymidylate synthesis, and a decrease in intracellular levels of the DNA-repair-associated pyridine nucleotide, nicotinamide adenine dinucleotide. In the liver, a synergistic lipotropic interaction between folate deficiency and methionine/choline deficiency was observed, confirming the metabolic inter-relationship between these nutrients. Taken together, the results suggest that folate deficiency interacts with methionine/choline deficiency to potentiate symptoms of methyl-donor deficiency and that alterations in folate-dependent thymidylate synthesis are related to DNA damage in lymphocytes. These metabolic aberrations may contribute to immune dysfunction with chronic feeding of methyl-donor-deficient diets.
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PMID:Diet-induced DNA damage and altered nucleotide metabolism in lymphocytes from methyl-donor-deficient rats. 247 30

The antipellagratic vitamin, nicotinamide, significantly suppressed urethane-induced malformations, when it was given intraperitoneally to pregnant JCL:ICR mice immediately after a single subcutaneous injection of urethane (1.0 mg/g) on the 9th day of gestation. The level of inhibition increased with the doses of nicotinamide: 33.0, 55.8, and 70.0% at doses of 0.1, 0.3, and 0.5 mg/g, respectively. Polydactyly and tail anomalies were markedly suppressed by the post-treatment with nicotinamide, while cleft palates were less effectively suppressed. Nicotinamide was still effective, when it was given during the period of 24-48 h after urethane treatment. Furthermore, dietary administration of nicotinamide also reduced urethane-induced malformations. The level of inhibition was 39.4 and 61.1% at 0.5 and 1.0% of nicotinamide in the diet, respectively. Higher doses of nicotinamide (3 and 5% in diet) also inhibited urethane-induced malformations, but not so effectively as lower doses. The inhibiting effects of nicotinamide on the spontaneous incidence of cleft lips and palates in CL/Fr mice were significant at a low dose (0.5% in diet), but not at a higher dose (1.0%). When [carbonyl-14C]nicotinamide was given to pregnant mice, nicotinamide and small amounts of nicotinamide adenine dinucleotide (NAD+), but not nicotinic acid, were detected chromatographically in the fetus and placenta, indicating that nicotinamide or NAD+ acts directly on the fetus to suppress urethane-induced malformations. A preliminary study revealed that urethane-induced lung tumorigenesis in JCL:ICR mice was also inhibited by post-treatment with nicotinamide in the diet. The level of inhibition was proportional to the dose of nicotinamide, that is, 35.0 and 62.8% at 1.0 and 2.5% of nicotinamide in the diet, respectively.
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PMID:Inhibiting effects of nicotinamide on urethane-induced malformations and tumors in mice. 296 97

Nicotinamide administered in the drinking water of male Fischer 344 rats increased the number of renal tubular cell tumors of rats treated with an i.p. injection of diethylnitrosamine (DEN) (25-mg/kg body weight). The incidence of kidneys with tumors in rats treated with DEN alone was 5%. In rats which received DEN and then were promoted with either 30 or 6.7 mM nicotinamide in their drinking water, the incidence of kidneys with tumors rose to 59 and 28%, respectively. Rats which were on 30 mM nicotinamide but did not receive DEN had no kidney tumors present. These results show that nicotinamide promoted DEN-induced renal tubular cell tumorigenesis.
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PMID:Promoting effect of nicotinamide on the development of renal tubular cell tumors in rats initiated with diethylnitrosamine. 315 47

Sprague-Dawley rat mammary gland is extremely sensitive to tumorigenesis by single or multiple doses of several polycyclic aromatic hydrocarbons. We obtained quantitative data on the in vitro mutagenic activation of several procarcinogens by 9000 g supernatant fraction (S9) from rat mammary gland using the Ames test. Mutagenic activation was shown to be dependent on a nicotinamide adenine dinucleotide phosphate (NADPH) generating system. An S9 preparation from mammary tissue of lactating Sprague-Dawley rats was shown to activate 2-aminoanthracene (2-AA). A polychlorinated biphenyl mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given to rats greatly raised the specific activity (revertant TA98 colonies/mg S9 protein) of the mammary tissue using 2-AA as a test carcinogen, and permitted detection of 2,4-diaminoanisole (DAA) and 2,7-diaminofluorene (DAF) activation. Procarcinogens 2-aminofluorine (2-AF), benzo[a]pyrene (BP) and aflatoxin (AFL) B1 were not detectably activated by mammary gland. Mutagenesis produced in mammary S9 activation of 2-AA, DAA or DAF was significantly inhibited by alpha-naphthoflavone (alpha NF) but was inhibited minimally by metyrapone (MP). Human mammary tumor cell lines (734B, SkBr3, MDA-MD-330) possessed inducible procarcinogen metabolizing activities similar to those found in S9 of rat mammary tissue. We demonstrated a simple and convenient use of the Ames test to characterize activation of many potential mutagens and carcinogens for mammary gland. When a test compound such as 2-AA was used, selective enzyme induction and inhibition was demonstrated.
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PMID:Procarcinogen activation by rat and human mammary extracts. 370 54

Albino noninbred weanling male and female rats were fed a basic grain diet (Group 1), a basic diet supplemented with 0.5% nicotinamide (Group 2), a basic diet containing 33% bracken fern (BF) (Group 3), or a basic diet supplemented with 33% BF and 0.5% nicotinamide (Group 4) for 58 weeks. Dietary nicotinamide decreased the BF-induced incidence of both intestinal and bladder tumorigenesis by about 40%. The inhibitory effect of nicotinamide on the BF-induced intestinal and bladder tumors was significant at p less than 0.05 and p less than 0.01, respectively.
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PMID:Protective effect of nicotinamide on bracken fern induced carcinogenicity in rats. 621 41

The effect of vitamin B-6 deficiency on in vivo host susceptibility to primary Moloney sarcoma virus (MSV)-induced tumor growth and to secondary challenge with MSB sarcoma cells was examined in mice. Female C57BL/6 mice, 6 weeks of age, were fed 20% casein diets with pyridoxine (PN) added at 1, 0.5, 0.1 or 0 mg/kg diet for 21 weeks. After 4 weeks of dietary treatment the mice were challenged with MSV. Vitamin B-6 deficiency resulted in an enhancement of tumor susceptibility as well as an increase in tumor size and regression time. The animals resistant to both MSV and MSV-transformed tumor cells ( MSB ) challenge showed splenic tumor development at necropsy 51 days after MSB challenge. Total incidence of MSV/ MSB /splenic tumors was 2/11, 2/11, 4/10 and 8/11 in animals fed PN 1, 0.5, 0.1 and 0 diets, respectively. Since MSV-induced tumors regressed spontaneously in immunocompetent hosts, the increased susceptibility to MSV oncogenesis in vitamin B-6-deficient animals suggests that reactivity of T cells and/or other effector cells is impaired in vitamin B-6-deficient animals suggests that reactivity of T cells and/or other effector cells is impaired in vitamin B-6 adequacy.
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PMID:The effect of vitamin B-6 deficiency on host susceptibility to Moloney sarcoma virus-induced tumor growth in mice. 672 63

Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD(+), as well as the assessment of niacin status are discussed. Since NAD(+) is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD(+) or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect against UV-induced tumors of the skin in mice, but data on similar preventive effects in humans are not available. NAM has been shown in vitro to have an antioxidant activity comparable to that of ascorbic acid. Data on niacin status and genomic stability in vivo in humans are limited and yield ambiguous results. Therefore, no firm conclusions with respect to optimal niacin intake are possible. As a consequence of oral niacin supplementation, however, NAM levels in the body may increase, which may result in inhibition of PARP-1 and increased genomic instability. More studies are needed to define an optimal level of niacin nutriture in relation to genomic stability and tumorigenesis.
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PMID:Niacin, poly(ADP-ribose) polymerase-1 and genomic stability. 1129 53

DNA damage induces p53 DNA binding activity, which affects tumorigenesis, tumor responses to therapies, and the toxicities of cancer therapies (B. Vogelstein, D. Lane, and A. J. Levine, Nature 408:307-310, 2000; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Both transcriptional and transcription-independent activities of p53 contribute to DNA damage-induced cell cycle arrest, apoptosis, and aneuploidy prevention (M. B. Kastan et al., Cell 71:587-597, 1992; K. H. Vousden and X. Lu, Nat. Rev. Cancer 2:594-604, 2002). Small-molecule manipulation of p53 DNA binding activity has been an elusive goal, but here we show that NAD(+) binds to p53 tetramers, induces a conformational change, and modulates p53 DNA binding specificity in vitro. Niacinamide (vitamin B(3)) increases the rate of intracellular NAD(+) synthesis, alters radiation-induced p53 DNA binding specificity, and modulates activation of a subset of p53 transcriptional targets. These effects are likely due to a direct effect of NAD(+) on p53, as a molecule structurally related to part of NAD(+), TDP, also inhibits p53 DNA binding, and the TDP precursor, thiamine (vitamin B(1)), inhibits intracellular p53 activity. Niacinamide and thiamine affect two p53-regulated cellular responses to ionizing radiation: rereplication and apoptosis. Thus, niacinamide and thiamine form a novel basis for the development of small molecules that affect p53 function in vivo, and these results suggest that changes in cellular energy metabolism may regulate p53.
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PMID:NAD+ modulates p53 DNA binding specificity and function. 1550 98

The erbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis and the progression of tumors such as breast cancer and ovarian cancer. Our investigation suggests that the anti-inflammatory agent N-(4-ethoxyphenol)-2-hydroxy-acid amide (SUCI02) reversibly represses tyrosine phosphorylation of erbB-2 in a dose-dependent manner, with half maximal inhibition occurring at a concentration of 21.05 micromol/L without reduced erbB-2 receptor expression. Activation of mitogen-activated protein kinase and protein kinase B, downstream molecules of the erbB-2-mediated signal transduction pathway, was inhibited following exposure to SUCI02. In contrast, tyrosine phosphorylation of epidermal growth factor receptor (EGFR) was relatively unaffected by SUCI02. Proliferation of erbB-2-overexpressing BT474 cells was inhibited to a greater extent than proliferation of EGFR-overexpressing A431 cells following exposure to SUCI02. SUCI02 induced cell cycle arrest in G(1) phase with upregulation of p27 and downregulation of pRb phosphorylation. Systemic administration of SUCI02 in nude mice resulted in inhibition of erbB-2 tyrosine kinase phosphorylation of subcutaneous human breast cancer BT474 xenografts. We conclude that SUCI02 inhibits erbB-2 tyrosine kinase phosphorylation in vitro and in vivo, shuts down the erbB-2 downstream pathway and induces cell cycle arrest in G(1) phase. These results suggest that SUCI02 is a potential novel anticancer agent that deserves further investigation. (Cancer Sci 2006; 97: 84-89).
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PMID:SUCI02 inhibits the erbB-2 tyrosine kinase receptor signaling pathway and arrests the cell cycle in G1 phase in breast cancer cells. 1636 26

We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein. We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5'untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis.
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PMID:SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. 1690 7


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