Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin B(6) has shown to be a potentially effective antioxidant agent, and dietary antioxidants are also frequently valuable inhibitors of clastogenesis and carcinogenesis. The purpose of the present work was to study the clastogenicity of different doses of vitamin B(6) and to examine the possible modulating effect of this vitamin on chromosomal damage induced by the antitumor agent doxorubicin in Wistar rats. Experimental groups were set up for pre- and simultaneous treatment with vitamin B(6) alone or in combination with DXR. The data obtained from administering different doses of vitamin B(6) (12.5-100 mg/kg b.w.) showed no significant increase in total chromosomal aberrations when compared with the negative control. The administration of two doses of 25 mg/kg b.w. or one dose of 50 mg/kg b.w. of vitamin B(6) before doxorubicin injection seemed equally effective in protecting cells against doxorubicin clastogenicity. The anticlastogenic effect of vitamin B(6) on DXR-induced chromosomal damage could be ascribed to its antioxidant properties. Vitamin B(6) was not clastogenic or cytotoxic in rat bone marrow cells and it plays a role in inhibiting the clastogenicity induced by DXR.
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PMID:Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B(6). 1848 96

Aldose reductase (AR; EC 1.1.1.21), an nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, has been shown to be involved in oxidative stress signaling initiated by inflammatory cytokines, chemokines and growth factors. Recently, we have shown that inhibition of this enzyme prevents the growth of colon cancer cells in vitro as well as in nude mice xenografts. Herein, we investigated the mediation of AR in the formation of colonic preneoplastic aberrant crypt foci (ACF) using azoxymethane (AOM)-induced colon cancer mice model. Male BALB/c mice were administrated with AOM without or with AR inhibitor, sorbinil and at the end of the protocol, all the mice were euthanized and colons were evaluated for ACF formation. Administration of sorbinil significantly lowered the number of AOM-induced ACF. Similarly, AR-null mice administered with AOM demonstrated significant resistance to ACF formation. Furthermore, inhibition of AR or knockout of AR gene in the mice significantly prevented AOM-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins as well as their messenger RNA. AR inhibition or knockdown also significantly decreased the phosphorylation of protein kinase C (PKC) beta2 and nuclear factor kappa binding protein as well as expression of preneoplastic marker proteins such as cyclin D1 and beta-catenin in mice colons. Our results suggest that AR mediates the formation of ACF in AOM-treated mice and thereby inhibition of AR could provide an effective chemopreventive approach for the treatment of colon cancer.
Carcinogenesis 2009 May
PMID:Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation. 1902 3

Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight.
Carcinogenesis 2009 Jan
PMID:Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. 1902 5

Proliferation and apoptosis of endothelial cells are crucial angiogenic processes that contribute to carcinogenesis and tumor progression. Emerging evidence implicates the regulation of proliferation and apoptosis by reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H(2)O(2)). In the present study, we investigated the roles of the ROS-generating Nox4- and Nox2-containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in proliferation of human endothelial cells by examining the impact of these enzyme systems on (1) specific proliferative and tumorigenic kinases, extracellular regulated kinase1/2 (ERK1/2) and Akt, (2) cytoskeletal organization, and (3) the mechanisms that influence cellular apoptosis. ROS production and the expression of NADPH oxidase subunit Nox4, but not Nox2, were markedly higher in proliferating than in quiescent endothelial cells. Addition of the H(2)O(2) scavenger catalase or downregulation of Nox4 protein with specific siRNA reduced ROS levels, cell proliferation, and ERK1/2 phosphorylation but had no effect on either cell morphology or caspase 3/7 activity. Although downregulation of Nox2 protein with siRNA also reduced ROS production and cell proliferation, it caused an increase in caspase 3/7 activity, reduced Akt phosphorylation, and caused cytoskeletal disorganization. Therefore, in endothelial cells, Nox4-derived H(2)O(2) activates ERK1/2 to promote proliferation, whereas Nox2-containing NADPH oxidase maintains the cytoskeleton and prevents apoptosis to support cell survival. Our study provides a new understanding of the molecular mechanisms that underpin endothelial cell survival and a rationale for the combined suppression of Nox4- and Nox2-containing NADPH oxidases for unwanted angiogenesis in cancer.
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PMID:NADPH oxidase isoform selective regulation of endothelial cell proliferation and survival. 1933 23

Reactive oxygen species (ROS) have been implicated in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance of many cancers. We evaluated the role of peroxiredoxin (Prx) I in TRAIL resistance governed by coupling of nicotinamide adenosine dinucleotide phosphate oxidase (Nox)-derived ROS signaling with the p38 mitogen-activated protein kinase (MAPK)/caspase-signaling cascade in liver cancer cells. Upregulated Prx I expression was found in neoplastic regions of human patient liver, and Prx I knockdown resulted in accelerated TRAIL-induced cell death in SK-Hep-1 human hepatoma cells. The TRAIL cytotoxicity by Prx I knockdown was dependent on activation of caspase-8/3 cascades, which was ablated by addition of inhibitors for p38 MAPK, ROS or Nox, suggesting the association with Nox-driven redox signaling. Furthermore, we found that Nox4 was constitutively expressed in both SK-Hep-1 cells and tumor regions of patient livers, knockdown of Nox4 expression could alleviate ROS generation and TRAIL-mediated cytotoxicity. In accordance with previous findings, increased activation of both p38 MAPK and caspase cascades by Prx I knockdown was inhibited by either Nox4 knockdown or SB203580 addition. Collectively, these data suggest that Prx I functions to block propagation of Nox-derived ROS signaling to the p38 MAPK/caspase/cell death cascade during TRAIL treatment and also provides a molecular mechanism by which Prx I contributes to TRAIL resistance in liver cancers.
Carcinogenesis 2009 Jul
PMID:Peroxiredoxin I contributes to TRAIL resistance through suppression of redox-sensitive caspase activation in human hepatoma cells. 1940 30

Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE(2) biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
Carcinogenesis 2009 Oct
PMID:HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells. 1963 28

Benzo[a]pyrene (B[a]P) is a ligand for the aryl hydrocarbon receptor (Ahr). After binding ligand, Ahr dimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) protein, and the dimer upregulates the transcription of Cyp1a1, Cyp1b1 and other enzymes involved in the metabolic activation of B[a]P. Arnt null mice die in utero. Mice in which Arnt deletion occurs constitutively in the epidermis die perinatally. In the current study, mice were developed in which the Arnt gene could be deleted specifically in adult skin epidermis. This deletion had no overt pathological effect. Homozygosity for a null reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase allele was introduced into the above mouse strain to render it more susceptible to tumor initiation by B[a]P. Deletion of Arnt in the epidermis of this strain completely prevented the induction of skin tumors in a tumor initiation-promotion protocol in which a single topical application of B[a]P acted as the tumor-initiating event, and tumor promotion was provided by repeated topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA). In contrast, deletion of Arnt did not prevent the induction of skin tumors in a protocol also using TPA as the promoter but using as the initiator N-methyl-N'-nitro-N-nitrosoguanidine, whose activity is unlikely to be affected by the activity of Ahr, Arnt or their target genes. These observations demonstrate that Arnt is required for tumor initiation by B[a]P in this system.
Carcinogenesis 2009 Nov
PMID:The aryl hydrocarbon receptor nuclear translocator (Arnt) is required for tumor initiation by benzo[a]pyrene. 1975 58

Mutations in the mitochondrial DNA (mtDNA) have been found to be present in several types of tumours including tumours of the large bowel. However, their role in cancer development and prognosis is still to be resolved. We used 2838 cases from a large Scottish colorectal cancer (CRC) case-control study to examine whether inherited genetic variation at the mtDNA influenced all-cause and CRC-specific mortality. We examined 140 tagging mtDNA variants including nine haplotypes commonly found in European populations. After applying three Cox proportional hazard models adjusted for American Joint Committee on Cancer (AJCC) stage, age and sex, three single nucleotide polymorphisms, two located in the 12S ribosomal RNA region (G752A and G1440A) and one in the nicotinamide adenine dinucleotide dehydrogenase subunit 2 region (ND2) region (G4770A), were statistically significantly associated with all-cause (Model I P-values: 0.0001, 0.002 and 0.002, respectively) and CRC-specific mortality (Model I P-values: 5 x 10(-5), 0.0003 and 0.0006, respectively). The H and U haplogroups were associated with an increased and decreased CRC risk, respectively, but with P-values of borderline significance and only after AJCC stage adjustment. In conclusion, the findings of the current study suggest a link between three common mtDNA variants and CRC prognosis. These findings are interesting and consistent with other biological knowledge but need to be confirmed through replication in independent cohorts.
Carcinogenesis 2010 Feb
PMID:Association between common mtDNA variants and all-cause or colorectal cancer mortality. 1994 68

Histone deacetylases (HDAC) have been under intense scientific investigation for a number of years. However, only recently the unique class III HDAC, sirtuins, have gained increasing investigational momentum. Originally linked to longevity in yeast, sirtuins and more specifically, SIRT1 have been implicated in numerous biological processes having both protective and/or detrimental effects. SIRT1 appears to play a critical role in the process of carcinogenesis, especially in age-related neoplasms. Similarly, alterations in circadian rhythms as well as production of the pineal hormone melatonin have been linked to aging and cancer risk. Melatonin has been found act as a differentiating agent in some cancer cells and to lower their invasive and metastatic status. In addition, melatonin synthesis and release occurs in a circadian rhythm fashion and it has been linked to the core circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes). Melatonin has also been associated with chronotherapy, the timely administration of chemotherapy agents to optimize trends in biological cycles. Interestingly, a recent set of studies have linked SIRT1 to the circadian rhythm machinery through direct deacetylation activity as well as through the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway. In this review, we provide evidence for a possible connection between sirtuins, melatonin, and the circadian rhythm circuitry and their implications in aging, chronomodulation, and cancer.
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PMID:Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. 2002 41

Sun protective measures can reduce numbers of both precancerous actinic keratoses and cutaneous squamous cell carcinomas within relatively short periods of time even in high-risk populations. Sunscreens, which tend to provide greater protection against shortwave UVB than against longer wavelength UVA radiation, can however provide only partial protection from the mutagenic and immune suppressive effects of sunlight. In large part, this reflects poor compliance with proper sunscreen application and reapplication. Skin cancer is by far the most common malignancy in Caucasian populations, and additional strategies to reduce the morbidity and economic burden of this disease are now urgently needed. Nicotinamide, the amide form of vitamin B3, is an inexpensive agent which is used for a variety of dermatological applications with little or no toxicity even at high doses. Nicotinamide has photoprotective effects against carcinogenesis and immune suppression in mice, and is photoimmunoprotective in humans when used as a lotion or orally. UV irradiation depletes keratinocytes of cellular energy and nicotinamide, which is a precursor of nicotinamide adenine dinucleotide, may act at least in part by providing energy repletion to irradiated cells.
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PMID:Photoprotective effects of nicotinamide. 2035 54


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