Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sarcotriol (ST) has been shown to be chemopreventive on 7,12-dimethyl-benz(a)anthracene (DMBA) initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor development in CD-1 mice in recent studies from our laboratory. The objective of this study was to determine the chemopreventive effects of ST on ultraviolet B (UVB)-induced skin tumor development in female SKH-1 hairless mice, an experimental model relevant to human skin cancer development, and its possible mechanisms of action. Female SKH-1 mice were divided into two groups: Control and ST treated. Control was topically treated with 100 microliter acetone and ST treated group administered with 30 microgram ST in 100 microliter acetone one hour before UVB exposure. For UVB-induced tumorigenesis, carcinogenesis was initiated and promoted by UVB (180 mJ/cm(2)). Group weights and tumor counts were taken once every week. After 30 weeks, mice were sacrificed and dorsal skin samples were collected. The proteins from the skin sample were further used for SDS-PAGE and Western blotting using specific antibodies against caspase-3, caspase-8, caspase-9 and p53. Tumor multiplicity was found 19.6, 5.2 in the control and ST treated groups respectively. Caspase-3, -8, -9 and p53 were significantly (P < 0.05) upregulated in ST treated group compared to Control group. Together, this study for the first time identifies the chemopreventive effects of ST in UVB-induced carcinogenesis possibly by inducing apoptosis and upregulating p53.
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PMID:Chemopreventive effects of sarcotriol on ultraviolet B-induced skin tumor development in SKH-1 hairless mice. 1846 28

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

Exposure to ultraviolet (UV) radiation has been associated with several acute and chronic conditions, including sunburn, edema, hyperplasia, immunosuppression, photoaging, and skin cancer. The role of naturally occurring phytochemicals in the prevention of such UV-related conditions has captured increased interest. Pomegranate ( Punica granatum L.) is a rich source of polyphenolics, which have been shown to exert anti-inflammatory, antioxidant, and anticarcinogenic activity in numerous in vivo and in vitro studies. This work investigated potential protective effects of a pomegranate fruit extract standardized to punicalagins against UVA- and UVB-induced damage in SKU-1064 human skin fibroblast cells. Pomegranate extract (PE), in a range from 5 to 60 mg/L, was effective at protecting human skin fibroblasts from cell death following UV exposure, likely related to a reduced activation of the pro-inflammatory transcription factor NF-kappaB, a downregulation of proapoptotic caspase-3, and an increased G0/G1 phase, associated with DNA repair. Higher polyphenolic concentrations (500-10000 mg/L) were needed to achieve a significant reduction in UV-induced reactive oxygen species levels and increased intracellular antioxidant capacity (from 1.9 to 8.6 muM Trolox equivalents/mL). Results from this study demonstrate the protective effects of PE against UVA- and UVB-induced cell damage and the potential use of pomegranate polyphenolics in topical applications.
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PMID:Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. 1871 70

In humans both UV-A and UV-B can cause gene mutations and suppress immunity, which leads to skin cancer, including melanoma. Inhibition of reactive oxygen species (ROS) and reactive nitrogen species (RNS) appears particularly promising as ROS and RNS production by both UV-A and UV-B contributes to inflammation, immunosuppression, gene mutation and carcinogenesis. We evaluated the effect of two lichen compounds, sphaerophorin (depside) and pannarin (depsidone) on pBR322 DNA cleavage induced by hydroxyl radicals (()OH), and by nitric oxide (NO), and their superoxide anion (O(2)(-)) scavenging capacity. In addition, we investigated the growth inhibitory activity of these compounds against human melanoma cells (M14 cell line). Sphaerophorin and pannarin showed a protective effect on plasmid DNA and exhibited a superoxide dismutase like effect. The data obtained in cell culture show that these lichen metabolites inhibit the growth of melanoma cells, inducing an apoptotic cell death, demonstrated by the fragmentation of genomic DNA (COMET and TUNEL Assays) and by a significant increase of caspase-3 activity, and correlated, at least in part, to the increase of ROS generation, These results confirm the promising biological properties of sphaerophorin and pannarin and encourage further investigations on their molecular mechanisms.
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PMID:Lichen metabolites prevent UV light and nitric oxide-mediated plasmid DNA damage and induce apoptosis in human melanoma cells. 1872 17

Melanoma is the most aggressive form of skin cancer, it originates from melanocytes and its incidence has increased in the last decade. Recent advances in the understanding of the underlying biology of the progression of melanoma have identified key signalling pathways that are important in promoting melanoma tumourigenesis, thus providing dynamic targets for therapy. One such important target identified in melanoma tumour progression is the Nuclear Factor-kappaB (NF-kappaB) pathway. In vitro studies have shown that NF-kappaB binding is constitutively elevated in human melanoma cultures compared to normal melanocytes. It has been found that a short cell-permeable peptide spanning the IKK-beta NBD, named NBD peptide, disrupted the association of NEMO with IKKs in vitro and blocked TNFalpha-induced NF-kappaB activation in vivo. In the present study we investigated the effect of the NBD peptide on NF-kappaB activity and survival of A375 human melanoma cells. We found that NBD peptide is able to inhibit the proliferation of A375 cells, which present constitutively elevated NF-kappaB levels. Inhibition of cell proliferation by NBD peptide was associated with direct inhibition of constitutive NF-kappaB DNA-binding activity and induction of apoptosis by activation of caspase-3 as confirmed by the cleavage and consequently inactivation of poly (ADP ribose) polymerase (PARP-1) known as the best marker of this process.
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PMID:NEMO-binding domain peptide inhibits proliferation of human melanoma cells. 1900 44

The c-Jun N-terminal kinase (JNK) signaling pathway is known to mediate both survival and apoptosis of tumor cells. Although JNK1 and JNK2 have been shown to differentially regulate the development of skin cancer, the underlying mechanistic basis remains unclear. Here, we demonstrate that JNK1, but not JNK2, interacts with and phosphorylates Myt1 ex vivo and in vitro. UVA induces substantial apoptosis in JNK wild-type (JNK(+/+)) or JNK2-deficient (JNK2(-/-)) mouse embryonic fibroblasts but has no effect on JNK1-deficient (JNK1(-/-)) cells. In addition, UVA-induced caspase-3 cleavage and DNA fragmentation were suppressed by the knockdown of human Myt1 in skin cancer cells. JNK1 deficiency results in suppressed Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA irradiation. In contrast, the absence of JNK2 induces Myt1 phosphorylation and caspase-3 cleavage in skin exposed to UVA. The overexpression of JNK1 with Myt1 promotes cellular apoptosis during the early embryonic development of Xenopus laevis, whereas the presence of JNK2 reduces the phenotype of Myt1-induced apoptotic cell death. Most importantly, JNK1(-/-) mice developed more UVA-induced papillomas than either JNK(+/+) or JNK2(-/-) mice, which was associated with suppressed Myt1 phosphorylation and decreased caspase-3 cleavage. Taken together, these data provide mechanistic insights into the distinct roles of the different JNK isoforms, specifically suggesting that the JNK1-mediated phosphorylation of Myt1 plays an important role in UVA-induced apoptosis and the prevention of skin carcinogenesis.
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PMID:c-Jun N-terminal kinase 1 phosphorylates Myt1 to prevent UVA-induced skin cancer. 1920 86

Lupeol, present in fruits and medicinal plants, is a biologically active compound that has been shown to have various pharmacological properties in experimental studies. In the present study, we demonstrated the modulatory effect of lupeol on 7,12-dimethylbenz[a]anthracene (DMBA)-induced alterations on cell proliferation in the skin of Swiss albino mice. Lupeol treatment showed significant (p < 0.05) preventive effects with marked inhibition at 48, 72, and 96 h against DMBA-mediated neoplastic events. Cell-cycle analysis showed that lupeol-induced G2/M-phase arrest (16-37%) until 72 h, and these inhibitory effects were mediated through inhibition of the cyclin-B-regulated signaling pathway involving p53, p21/WAF1, cdc25C, cdc2, and cyclin-B gene expression. Further lupeol-induced apoptosis was observed, as shown by an increased sub-G1 peak (28%) at 96 h, with upregulation of bax and caspase-3 genes and downregulation of anti-apoptotic bcl-2 and survivin genes. Thus, our results indicate that lupeol has novel anti-proliferative and apoptotic potential that may be helpful in designing strategies to fight skin cancer.
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PMID:Lupeol induces p53 and cyclin-B-mediated G2/M arrest and targets apoptosis through activation of caspase in mouse skin. 1923 20

Sarcophine-diol (SD), a structural modifications of sarcophine, has shown chemopreventive effects on 7,12-dimethylbenz(a)anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted skin tumor developments in mice. Tumorigenesis is associated with uncontrolled cell growth and loss of apoptosis. In the present study, the effects of SD on cell growth and apoptosis in human epidermoid carcinoma A431 cells were determined to assess whether SD could inhibit cell growth and/or induce apoptosis, thus elucidating possible mechanism of action. MTT assay was used for cell viability; bromodeoxyuridine incorporation assay was used for cell proliferation; fluorescence-activated cell sorting analysis of annexin V/propidium iodide staining and TUNEL assay were used for determining apoptotic cells; Western blot analysis was used for determining the expression of caspase-3 and colorimetric caspase activity assays were used for determination of caspase-3, -8, and -9 activity. The results showed that SD treatment at concentration of 200 to 600 microM resulted in a concentration-dependent decrease in cell viability and cell proliferation in A431 cells, which largely inhibited cell growth. Sarcophine-diol treatment induced a strong apoptosis and significantly (P < .05) increased DNA fragmentation in A431 cells. Furthermore, SD treatment significantly (P < .05) increased the activity and expression of caspase-3 through activation of upstream caspase-8 in A431 cells rather than the activation of caspase 9. Sarcophine-diol treatment is relatively much less cytotoxic in monkey kidney normal CV-1 cells. These results suggest that SD decreases cell growth and induces apoptosis through caspase-dependent extrinsic pathway in A431 cells, and this may contribute to its overall chemopreventive effects in mouse skin cancer models.
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PMID:Sarcophine-diol, a Chemopreventive Agent of Skin Cancer, Inhibits Cell Growth and Induces Apoptosis through Extrinsic Pathway in Human Epidermoid Carcinoma A431 Cells. 1925 48

Scopoletin, an alkaloid separated from ethanolic extract of the medicinal plant, Gelsemium sempervirens (Fam: Loganiaceae) has been reported to have anti-cancer potentials. The synthetic coumarin (4-Methyl-7 hydroxy coumarin) derived from resorcinol and ethyl aceto-acetate in presence of concentrated sulphuric acid is structurally close to scopoletin, being a coumarin derivative. Whether this synthetic compound also has anti-cancer potentials has been evaluated in vivo on DMBA (7,12-Dimethylbenz[a]anthracene) induced skin cancer in mice by analyzing results of several cytogenetic endpoints, Comet assay, and fluorescence activated cell sorting (FACS). Further, expressions of signal proteins like Aryl hydrocarbon receptor , p53, PCNA, Akt, Bcl-2, Bcl-xL, Bad, Bax, NF-kappaB Apaf, IL-6, Cytochrome-c, Caspase-3 and Caspase-9 were studied by immunoblot analysis along with histology of skin and immuno-histochemical localization of Aryl hydrocarbon receptor and PCNA in DMBA treated mice vis-a-vis carcinogen treated synthetic coumarin fed mice. Feeding of this synthetic coumarin induced positive modulations in expression of all biomarkers in DMBA administered mice, giving clues on its possible signaling pathway(s) - primarily through down-regulation of Aryl hydrocarbon receptor and PCNA and up-regulation of apoptotic proteins like Bax, Bad, Cytochrome c, Apaf, Caspase-3 and Caspase-9, resulting in an appreciable reduction in growth of papilloma in mice. Therefore, this synthetic coumarin shows promise for use in cancer therapy, particularly in skin cancer.
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PMID:A synthetic coumarin (4-methyl-7 hydroxy coumarin) has anti-cancer potentials against DMBA-induced skin cancer in mice. 1939 33

Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.
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PMID:Plumbagin induces cell death through a copper-redox cycle mechanism in human cancer cells. 1950 95


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