A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by suppression of oxidative stress

Nakamura, Yoshimasa; Kawamoto, Norihiko; Ohto, Yoshimi; Torikai, Koji; Murakami, Akira; Ohigashi, Hajime

doi:10.1016/s0304-3835(99)00048-8

Cited by 54 publications

(33 citation statements)

References 24 publications

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“…It is well recognized that DMBA or TPA treatment can induce oxidative stress (Nakamura et al, 1999;Khajuria et al, 1998). We have previously demonstrated that TPA application induced rapid oxidative stress at the subcellular level as indicated by increased 4-HNE modi®ed protein levels in both mitochondria and nuclei in a B6C3 carcinogenesis mouse model (Zhao et al, 2001b).…”

Section: Dmba/tpa Treatment Induced Oxidative Stressmentioning

confidence: 99%

Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

et al. 2002

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Previous studies in our laboratories demonstrated that overexpression of manganese superoxide dismutase (MnSOD) suppressed both the incidence and multiplicity of papillomas in a DMBA/TPA multi-stage skin carcinogenesis model. The activity of activator protein-1 (AP-1), which is associated with tumor promotion, was reduced in MnSOD transgenic mice overexpressing MnSOD in the skin, suggesting that MnSOD may reduce tumor incidence by suppressing AP-1 activation. In the present study, we report that reduction of MnSOD by heterozygous knockout of the MnSOD gene (Sod2 7/+, MnSOD KO) increased the levels of oxidative damage proteins and the activity of AP-1 following TPA treatment. RNA levels of ornithine decarboxylase (ODC) were also increased, suggesting an increase in cell proliferation in the KO mice. Histological examination con®rmed that the number of proliferating cells in DMBA/TPA-treated mouse skin were higher in the KO mice. Interestingly, histological examination also demonstrated greater numbers of apoptotic cells in the KO mice after DMBA/TPA treatment. Evidence of apoptosis, including DNA fragmentation, cytochrome c release from mitochondria, and caspase 3 activation were also observed by biochemical assays of the skin tissues. Apoptosis was associated with an increase in nuclear levels of p53 as determined by Western analysis. Quantitative immunogold ultrastructural analysis con®rmed that p53 immunoreactive protein levels were increased to a greater level in the nuclei of epidermal cells from MnSOD KO mice compared to epidermal nuclei from wild type mice similarly treated. Moreover, p53 levels further increased in the mitochondria of DMBA/TPA treated mice, and this increase was much greater in the MnSOD KO than in the wild type mice, suggesting a link between MnSOD de®ciency and mitochondrial-mediated apoptosis. Pathological examination reveals no dierence in the incidence and frequency of papillomas comparing the KO mice and their wild type littermates. Taken together, these results suggest that: (1) MnSOD de®ciency enhanced TPAinduced oxidative stress and AP-1 and p53 levels, consistent with the increase in both proliferation and apoptosis events in the MnSOD KO mice, and (2) increased apoptosis may negate increased proliferation in the MnSOD de®cient mice during an early stage of tumor development.

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Section: Dmba/tpa Treatment Induced Oxidative Stressmentioning

confidence: 99%

Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

et al. 2002

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“…It is well recognized that DMBA or TPA treatment can cause oxidative stress (18,19). We have previously shown that TPA application induced rapid oxidative stress at the subcellular level as indicated by increased formation of carbonyl groups (aldehydes and ketones), a standard biomarker of oxidative damage, which are formed in the amino side chains of proteins (13).…”

Section: Antioxidant Approach For Skin Carcinogenesis Reductionmentioning

confidence: 99%

A Mechanism-Based Antioxidant Approach for the Reduction of Skin Carcinogenesis

Zhao¹,

et al. 2005

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Studies in our laboratories showed that overexpression of manganese superoxide dismutase (MnSOD) reduced tumor incidence in a multistage skin carcinogenesis mouse model. However, reduction of MnSOD by heterozygous knockout of the MnSOD gene (MnSOD KO) did not lead to an increase in tumor incidence, because a reduction of MnSOD enhanced both cell proliferation and apoptosis. The present study extends our previous studies in the MnSOD KO mice and shows that apoptosis in mouse epidermis occurred prior to cell proliferation (6 versus 24 hours) when treated with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the possibility that a timed administration of SOD following apoptosis but before proliferation may lead to suppression of tumor incidence, we applied a SOD mimetic (MnTE-2-PyP 5+ ) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP 5+ suppressed the level of protein carbonyls and reduced the activity of activator protein-1 and the level of proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Histologic examination confirmed that MnTE-2-PyP 5+ suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP 5+ before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention. (Cancer Res 2005; 65(4): 1401-5)

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“…(2), hydrogen peroxide (H 2 O 2 ) (3), PGE 2 and PGF 2␣ (4), cyclooxygenase (COX)-2 expression (5) as well as the release of tumor necrosis factor ␣ (6). Thus, leukocyte activation resulting in ROS generation coupled to excessive production of chemotactic factors may play an important role in chronic inflammation and hyperplasia in mouse skin (7,8). In addition, ROS production by double or multiple TPA treatments is closely associated with the metabolic activation of proximate carcinogens (9,10) and the increased levels of oxidized DNA bases (11)(12)(13).…”

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confidence: 99%

Ebselen, a Glutathione Peroxidase Mimetic Seleno-organic Compound, as a Multifunctional Antioxidant

Nakamura

Feng

Kumagai

et al. 2002

Journal of Biological Chemistry

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150

111

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Ebselen, a seleno-organic compound showing glutathione peroxidase-like activity, is one of the promising synthetic antioxidants. In the present study, we investigated the antioxidant activities of ebselen using a 12-Otetradecanoylphorbol-13-acetate (TPA)-treated mouse skin model. Double pretreatments of mouse skin with ebselen significantly inhibited TPA-induced formation of thiobarbituric acid-reacting substance, known as an overall oxidative damage biomarker, in mouse epidermis, suggesting that ebselen indeed acts as an antioxidant in mouse skin. The antioxidative effect of ebselen is attributed to its selective blockade of leukocyte infiltration and activation leading to attenuation of the H 2 O 2 level. In in vitro studies, ebselen inhibited TPA-induced superoxide generation in differentiated HL-60 cells and lipopolysaccharide-induced cyclooxygenase-2 protein expression in RAW 264.7 cells. In addition, we demonstrated for the first time that ebselen potentiated phase II enzyme activities, including NAD(P)H:(quinone-acceptor) oxidoreductase1 and glutathione S-transferase in cultured hepatocytes and in mouse skin. These results strongly suggest that ebselen, a multifunctional antioxidant, is a potential chemopreventive agent in inflammation-associated carcinogenesis.

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A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by suppression of oxidative stress

Cited by 54 publications

References 24 publications

Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

A Mechanism-Based Antioxidant Approach for the Reduction of Skin Carcinogenesis

Ebselen, a Glutathione Peroxidase Mimetic Seleno-organic Compound, as a Multifunctional Antioxidant

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