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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of apoptosis is one of the most active strategies in cancer chemoprevention and the ability of medicinal plants in this regard has attracted major research interest. The present study was designed to investigate the apoptosis inducing capacity of an ethanolic neem leaf extract (ENLE) during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis using the apoptosis-associated proteins Bcl-2, Bim, caspase 8 and caspase 3 as markers. Topical application of DMBA to the hamster cheek pouch for 14 weeks resulted in well developed squamous cell carcinomas associated with increased expression of Bcl-2 and decreased expression of Bim, caspase 8 and caspase 3. Administration of ENLE inhibited DMBA-induced hamster buccal pouch (HBP) carcinogenesis, as revealed by the absence of neoplasms, with induction of Bim and caspases 8 and 3 and inhibition of Bcl-2 expression. Our results suggest that the chemopreventive effects of ENLE may be mediated by induction of apoptosis.
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PMID:Ethanolic neem (Azadirachta indica) leaf extract induces apoptosis in the hamster buccal pouch carcinogenesis model by modulation of Bcl-2, Bim, caspase 8 and caspase 3. 1643 3

Previously, we found that the H1 histamine receptor antagonist diphenhydramine induces apoptosis in human acute T-lymphocytic leukemia cells. Since histamine has been shown to act as a growth factor in malignant melanoma cells, we decided to evaluate the in vitro effect of diphenhydramine and other H1 histamine receptor antagonists, such as terfenadine, astemizol and triprolidine on four malignant human melanoma cell lines. These antagonists were found to induce apoptotic cell death in all four melanoma cell lines. Apoptosis was determined by assessment of phosphatidylserine exposure on the surface of the cells and nuclear fragmentation. Importantly, H1 antagonist treatments did not adversely affect the viability of human melanocytes and murine fibroblasts at the same doses and duration of exposure. Treatment of melanoma cells with terfenadine induced DNA damage and caspases 2, 3, 6, 8 and 9 activation. Furthermore, the general caspase inhibitor (z-VAD-FMK) and a selective inhibitor of caspase-2 (z-VDVAD-FMK) protected melanoma cells from terfenadine-induced apoptosis. In contrast, the caspase-8 inhibitor (z-IETD-FMK) was ineffective. In addition, we found that mitochondria are involved in TEF-induced apoptosis, characterized by the dissipation of the mitochondrial transmembrane potential, the release of cytochrome c into the cytosolic compartment and caspase-9 activation. On the basis of these results we conclude that H1 histamine receptor antagonists induce apoptosis in human melanoma cells but not in normal melanocytes and embryonic murine fibroblasts; this apoptosis appears to be caspase-2-dependent and involves the mitochondrial pathway. The present results may contribute to the elaboration of novel therapeutic strategies for the treatment of malignant human melanoma.
Carcinogenesis 2006 Sep
PMID:H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells. 1656 56

Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide - the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor-->phosphatidylinositol 3-kinase pathway.
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PMID:Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide. 1668 48

Chemoresistance has been one of the major problems in anticancer therapy. In our effort to find a potential molecular target for overcoming the chemoresistance in prostate cancer, a promising anticancer drug trichostatin A (TSA) induced cell death was found to be compromised by enhanced NF-kappaB activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-kappaB activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IkappaBalpha and p65/RelA (but not p50/NF-kappaB1) in the cytoplasm. Clonogenic cell survival and soft agar assays further confirmed the increased TSA chemosensitivity of 267B1/K-ras cells by ProI treatment. Moreover, dominant negative mutant of IKKbeta, IkappaBalpha and p65 enhanced the chemosensitization, too. Unexpectedly, using LY294002 and PD98059, phosphatidylinositol-3-kinase and mitogen-activated protein kinase were also implied in TSA chemoresistance through NF-kappaB activation, while these compounds had showed no effect on radiosensitization in the cells. On the other hand, together with TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, activations of caspase-8 and caspase-3 by TSA and ProI were noticed, suggesting the involvement of apoptotic process in chemosensitization of 267B1/K-ras cells. Altogether, these results suggest that blocking the NF-kappaB activation pathway could be an efficient target for improving the TSA chemosensitization and applying to the development of anticancer therapeutics in Ki-Ras-overexpressing tumorigenic cells, including prostate cancer.
Carcinogenesis 2006 Nov
PMID:NF-kappaB inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells. 1677 37

Chronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this review, we provide and discuss the pathomechanisms of arsenic skin cancer and the relationship to its characteristic figures. Such information is critical for understanding the molecular mechanism for arsenic carcinogenesis in other internal organs.
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PMID:Arsenic carcinogenesis in the skin. 1680 64

UV light (UV-C) is a potent inducer of the c-fos gene. Cells lacking c-Fos are hypersensitive to the cytotoxic effect of UV-C indicating a protective role of c-fos induction. Here we show that cells deficient in c-Fos (fos-/-) are unable to remove cyclobutane pyrimidine dimers (CPDs) from DNA and undergo apoptosis at high frequency via the Fas pathway. We also show that in c-Fos-deficient cells the activation of c-Jun N-terminal kinase (JNK) by UV-C differs from the wild-type (wt, fos+/+). In wt cells JNK activation is transient, returning to control level 5-8 h after treatment, whereas in c-Fos-deficient cells JNK activation was long-lasting and did not return to control level. Inhibition of early JNK activation by the JNK inhibitor SP600125 attenuated CPD repair and increased UV-C induced apoptosis whereas inhibition of late JNK activation attenuated the apoptotic response of c-Fos-deficient cells. Late and sustained activation of JNK resulted in upregulation of fas (CD95, apo-1) ligand and induction of caspase 8-dependent apoptosis. The data indicate that the immediate-early induction of the JNK/c-fos pathway stimulates the repair of UV-C induced DNA lesions that protects against apoptosis. If this does not occur, cells do not recover from transcription blockage leading, as shown for c-Fos-deficient cells, to a reduced expression of MKP1, sustained JNK activation and fasL overexpression that finally results in activation of the death receptor pathway. The data support the hypothesis that non-repaired DNA damage is the cause for the late and sustained activation of the MAP kinase pathway in response to genotoxins.
Carcinogenesis 2007 Jan
PMID:A role for UV-light-induced c-Fos: Stimulation of nucleotide excision repair and protection against sustained JNK activation and apoptosis. 1682 84

In this work we have studied how dietary fat affects aging-related changes in a number of factors that regulate rat hepatic apoptosis. Animals were fed lifelong with two experimental diets containing either virgin olive oil or sunflower oil as dietary fat. Caspases of the intrinsic and extrinsic pathways of apoptosis, Bcl-2 and Bax polypeptide levels, and plasma membrane neutral sphingomyelinase activity were determined at 6, 12, and 24 months of age. Caspase-8/10 activity (a marker of the extrinsic pathway) was not affected by either aging or dietary fat, but activities of both caspase-9 (a marker of the intrinsic pathway) and caspase-3 (an executioner caspase) were significantly depressed in liver from animals fed on a sunflower oil-based diet. These decreases were not observed in animals fed with a diet based on virgin olive oil, which also resulted in significantly lower Bcl-2/Bax ratios. On the other hand, in comparison with sunflower, dietary olive oil decreased oxidative stress in liver from aged rats, resulting in lower levels of membrane hydroperoxides and higher coenzyme Q levels in plasma membrane. Plasma membrane Mg(2+)-dependent neutral sphingomyelinase was strongly activated in aged rats fed on the sunflower oil diet, but no aging-related increase was observed in animals fed on the olive oil diet. Our results support that dietary oil can alter significantly the susceptibility of hepatocytes to different apoptotic stimuli by altering both pro- and anti-apoptotic mediators, which reinforces the importance of the diet in aging studies. Because virgin olive oil may increase susceptibility of hepatocytes to apoptosis induced through the intrinsic pathway under conditions of decreased oxidative stress, our results may have important implications to understand the potential beneficial effects of that edible oil against liver carcinogenesis during aging.
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PMID:Differential regulation of hepatic apoptotic pathways by dietary olive and sunflower oils in the aging rat. 1704 86

The identification of proteins, which exhibit different levels in normal, premalignant, and malignant lung cells, could improve early diagnosis and intervention. We compared the levels of proteins in normal human bronchial epithelial (NHBE) and tumorigenic HBE cells (1170-I) by high-throughput immunoblotting (PowerBlot Western Array) using 800 monoclonal antibodies. This analysis revealed that 87 proteins increased by >2-fold, and 45 proteins decreased by >2-fold, in 1170-I compared with NHBE cells. These proteins are involved in DNA synthesis and repair, cell cycle regulation, RNA transcription and degradation, translation, differentiation, angiogenesis, apoptosis, cell adhesion, cytoskeleton and cell motility, and the phosphatidylinositol 3-kinase signaling pathway. Conventional Western blotting using lysates of normal, immortalized, transformed, and tumorigenic HBEs and non-small cell lung cancer cell lines confirmed some of these changes. The expression of several of these proteins has been then analyzed by immunohistochemistry in tissue microarrays containing 323 samples, including normal bronchial epithelium, hyperplasia, squamous metaplasia, dysplasias, squamous cell carcinomas, atypical adenomatous hyperplasia, and adenocarcinomas from 144 patients. The results of the immunohistochemical studies correlated with the Western blotting findings and showed gradual increases (caspase-8, signal transducers and activators of transcription 5, and p70s6K) or decrease (E-cadherin) in levels with tumor progression. These results indicate that the changes in proteins detected in this study may occur early in lung carcinogenesis and persist in lung cancer. In addition, some of the proteins detected by this approach may be novel biomarkers for early detection of lung cancer and novel targets for chemoprevention or therapy.
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PMID:Identification and validation of differences in protein levels in normal, premalignant, and malignant lung cells and tissues using high-throughput Western Array and immunohistochemistry. 1714 64

This study examined whether suppression of mammary gland carcinogenesis elicited by low doses of tamoxifen (TAM) can be enhanced by concomitant treatment of rats with indole-3-carbinol (I3C), a component of cruciferous vegetables and a dietary supplement used for its putative antiestrogenicity. Two weeks after one oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 65 mg/kg body weight, female Sprague-Dawley rats started treatment with TAM (10 microg/rat) by subcutaneous injection, I3C (250 mg/kg body weight) by oral gavage, TAM+I3C or their respective vehicles three times per week, for up to 20 weeks. Significant increases in the median latency of malignant mammary tumors and decreases in the mean tumor mass per rat were due to TAM. Significant decreases in the mean tumor number per rat in TAM, I3C and TAM+I3C-treated rats indicated a cooperative effect of the two compounds. In both DMBA-initiated and uninitiated rats, significant increases in the ratios of liver to body weight in I3C and TAM+I3C-treated groups coincided with I3C-dependent increases of hepatic cytochrome P450 levels and activities (1A1, 1A2 and 2B1/2). The ratios of uterus to body weight decreased with the number of treatments and the decreases effected by TAM were greater than those by I3C. The levels of circulating estrone were increased in response to I3C treatment and were greater in DMBA-initiated rats than in uninitiated rats, which may contribute to the preventive effect of I3C. Chemoprevention may be accomplished through up-regulation of apoptotic enzyme (caspase) activities in the mammary gland or mammary tumors. Treatment with TAM, I3C or TAM+I3C had no effect on caspase-3&7, caspase-6, caspase-8 and caspase-9 activities in the mammary tumors or mammary gland of tumor-bearing rats or that of uninitiated rats. In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities, suggesting an I3C-mediated protective effect. Even though I3C alone is a much less effective suppressing agent of mammary carcinogenesis than TAM, I3C in combination with TAM does not weaken but may foster the benefits of chemoprevention with TAM.
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PMID:Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination. 1729 89

To isolate pharmacologically safe compounds that can induce apoptosis of tumor cells, leaves of an aromatic plant (Zanthoxylum schinifolium), which are widely used as a food flavor and herbal medicine in Korea and Japan, were sequentially extracted by organic solvents. An apoptogenic ingredient in the methylene chloride extract was further purified by silica gel column chromatography and identified as auraptene (AUR). The IC(50) value of AUR against Jurkat T cells was 16.5 microg/ml. After the treatment of Jurkat T cells with AUR, the endoplasmic reticulum (ER) stress-mediated activation of caspase-12 and -8 and subsequent apoptotic events including c-Jun N-terminal kinase (JNK) activation, cleavage of FLICE inhibitory protein and Bid, mitochondrial cytochrome c release, activation of caspase-9 and -3, degradation of poly (ADP-ribose) polymerase and apoptotic DNA fragmentation were induced in a dose-dependent manner. The cytotoxicity of AUR was not blocked by the anti-Fas neutralizing antibody ZB-4. The AUR-induced cytotoxicity and apoptotic events were abrogated by ectopic over-expression of Bcl-xL or addition of the pan-caspase inhibitor z-VAD-fmk. The individual or simultaneous addition of the m-calpain inhibitor (E64d), JNK inhibitor (SP600125) and mitochondrial permeability transition pore inhibitor (CsA) failed to prevent apoptotic events including caspase-8 activation and Bid cleavage, unless the caspase-8 inhibitor (z-IETD-fmk) was combined, whereas AUR-induced caspase-12 activation was sustained even in the concomitant presence of z-IETD-fmk. These results demonstrated that the apoptotic effect of AUR on Jurkat T cells was exerted by the ER stress-mediated activation of caspase-8, and the subsequent induction of mitochondria-dependent or -independent activation of caspase cascade, which could be suppressed by Bcl-xL.
Carcinogenesis 2007 Jun
PMID:Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. 1730 Oct 64


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