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John Digiovanni - One of the best experts on this subject based on the ideXlab platform.
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inhibition of skin Tumor Promotion by tpa using a combination of topically applied ursolic acid and curcumin
Molecular Carcinogenesis, 2019Co-Authors: Lisa Tremmel, Okkyung Rho, Thomas J. Slaga, John DigiovanniAbstract:Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin Tumor Promotion using the mouse two-stage skin carcinogenesis model. In short-term experiments, the combination of UA + Curc given topically prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF-κB p50, Src, c-Jun, Rb, and IκBα. Levels of c-Fos, c-Jun, and Cox-2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL-1β, IL-6, IL-22, and CXCL2. Furthermore, results from skin Tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin Tumor Promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on Tumor free survival, Tumor size, and Tumor weight, although Tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.
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evaluation of pentacyclic triterpenes found in perilla frutescens for inhibition of skin Tumor Promotion by 12 o tetradecanoylphorbol 13 acetate
Oncotarget, 2015Co-Authors: Jiyoon Cho, Thomas J. Slaga, Okkyung Rho, Lisa Tremmel, Andrew M Camelio, Dionicio Siegel, John DigiovanniAbstract:A series of pentacyclic tritperpenes found in Perilla frutescens (P. frutescens), including ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on epidermal cell signaling, proliferation, and skin inflammation in relation to their ability to inhibit skin Tumor Promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and compared to UA as the prototype compound. All compounds were given topically 30 min prior to each TPA application and significantly inhibited skin Tumor Promotion. 3-epiCA and MA were significantly more effective than UA at inhibiting Tumor development. All of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds also reduced skin inflammation (assessed by infiltration of mast cells and T-cells) and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were again more effective than UA. The greater ability of 3-epiCA and MA to inhibit skin Tumor Promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation (i.e., phosphorylation) of IGF-1R, STAT3 and Src. Further study of these compounds, especially 3-epiCA and MA, for chemopreventive activity in other cancer model systems is warranted.
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metformin inhibits skin Tumor Promotion in overweight and obese mice
Cancer Prevention Research, 2014Co-Authors: Allyson L Checkley, Linda M Beltran, Okkyung Rho, Jiyoon Cho, Joe M Angel, Jorge Blando, Stephen D Hursting, John DigiovanniAbstract:In the present study, the ability of metformin to inhibit skin Tumor Promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in mice maintained on either an overweight control diet or an obesity-inducing diet. Rapamycin was included for comparison, and a combination of metformin and rapamycin was also evaluated. Metformin (given in the drinking water) and rapamycin (given topically) inhibited development of both papillomas and squamous cell carcinomas in overweight and obese mice in a dose-dependent manner. A low-dose combination of these two compounds displayed an additive inhibitory effect on Tumor development. Metformin treatment also reduced the size of papillomas. Interestingly, all treatments seemed to be at least as effective for inhibiting Tumor formation in obese mice, and both metformin and rapamycin were more effective at reducing Tumor size in obese mice compared with overweight control mice. The effect of metformin on skin Tumor development was associated with a significant reduction in TPA-induced epidermal hyperproliferation. Furthermore, treatment with metformin led to activation of epidermal AMP-activated protein kinase (AMPK) and attenuated signaling through mTOR complex (mTORC)-1 and p70S6K. Combinations of metformin and rapamycin were more effective at blocking epidermal mTORC1 signaling induced by TPA consistent with the greater inhibitory effect on skin Tumor Promotion. Collectively, the current data demonstrate that metformin given in the drinking water effectively inhibited skin Tumor Promotion in both overweight and obese mice and that the mechanism involves activation of epidermal AMPK and attenuated signaling downstream of mTORC1. Cancer Prev Res; 7(1); 54–64. ©2013 AACR.
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rapamycin is a potent inhibitor of skin Tumor Promotion by 12 o tetradecanoylphorbol 13 acetate
Cancer Prevention Research, 2011Co-Authors: Allyson L Checkley, Okkyung Rho, Tricia Moore, S D Hursting, John DigiovanniAbstract:Aberrant activation of phosphoinositide-3-kinase (PI3K)/Akt signaling has been implicated in the development and progression of multiple human cancers. During the process of skin Tumor Promotion induced by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), activation of epidermal Akt occurs as well as several downstream effectors of Akt, including the activation of mTORC1. Rapamycin, an established mTORC1 inhibitor, was used to further explore the role of mTORC1 signaling in epithelial carcinogenesis, specifically during the Tumor Promotion stage. Rapamycin blocked TPA-induced activation of mTORC1 as well as several downstream targets. In addition, TPA-induced epidermal hyperproliferation and hyperplasia were inhibited in a dose-dependent manner with topical rapamycin treatments. Immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin also significantly decreased the number of infiltrating macrophages, T cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Using a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and TPA as the promoter, rapamycin (5-200 nmol per mouse given topically 30 minutes prior to TPA) exerted a powerful antipromoting effect, reducing both Tumor incidence and Tumor multiplicity. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited further growth. Overall, the data indicate that rapamycin is a potent inhibitor of skin Tumor Promotion and suggest that signaling through mTORC1 contributes significantly to the process of skin Tumor Promotion. The data also suggest that blocking this pathway either alone or in combination with other agents targeting additional pathways may be an effective strategy for prevention of epithelial carcinogenesis.
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constitutive expression of insulin like growth factor 1 in epidermal basal cells of transgenic mice leads to spontaneous Tumor Promotion
Cancer Research, 2000Co-Authors: John Digiovanni, Linda M Beltran, David Bol, Erik Wilker, Steve Carbajal, Samantha Moats, Angel Ramirez, Jose L Jorcano, Kaoru KiguchiAbstract:Transgenic mice overexpressing insulin-like growth factor-1 (IGF-1) in the basal layer of skin epidermis were generated using the bovine keratin 5 promoter (BK5). Neonatal transgenic mice were slightly smaller at birth and exhibited early ear unfolding, wrinkled and thickened skin, and slightly enlarged ears compared with nontransgenic littermates. Morphological evaluation of the skin revealed that persistent overexpression of IGF-1 in the basal layer of the epidermis resulted in epidermal hyperplasia, hyperkeratosis, and an increased labeling index that persisted in adult mice. Phenotypic changes observed in skin were associated with transgene expression in the basal layer of the epidermis and activation of the IGF-1 receptor. Squamous papillomas (some of which converted to carcinomas) developed in a significant proportion (approximately 50%) of older BK5.IGF-1 mice. Treatment of BK5.IGF-1 transgenic mice with multiple topical applications of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, in the absence of Tumor initiation led to the development of additional skin papillomas. Furthermore, treatment of BK5.IGF-1 transgenic mice with an initiating dose of 7,12-dimethylbenz[a]anthracene only led to the formation of additional papillomas in the absence of Promotion. In two-stage carcinogenesis experiments, BK5.IGF-1 transgenic mice developed 7-fold more papillomas than nontransgenic littermates. Phosphatidylinositol-3-kinase and protein kinase B (Akt) activities were elevated (3-4-fold), and mitogen-activated protein kinase activity was elevated approximately 1.7-fold in the epidermis of transgenic mice compared with nontransgenic mice. In addition, UV light-induced epidermal apoptosis was significantly suppressed in BK5.IGF-1 transgenic mice. These data suggest that persistent activation of IGF-1 receptor signaling pathways in basal epithelial cells leads to spontaneous Tumor Promotion and that up-regulation of both mitogenic and cell survival signaling pathways may play an important role in the action of IGF-1 in this model system.
Sarwat Sultana - One of the best experts on this subject based on the ideXlab platform.
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glycyrrhizin exhibits potential chemopreventive activity on 12 o tetradecanoyl phorbol 13 acetate induced cutaneous oxidative stress and Tumor Promotion in swiss albino mice
Journal of Enzyme Inhibition and Medicinal Chemistry, 2007Co-Authors: Sahar Rahman, Sarwat SultanaAbstract:Glycyrrhizin and its aglycone, glycyrrhetic acid has been found useful for various therapeutic purposes. Glycyrrhizin has been shown to possess many physiological functions like anti-inflammatory activity, detoxification and inhibition of carcinogenic promoters. 12-O-Tetradecanoyl phorbol-13-acetate (TPA), a well-known phorbal ester is known for its Tumor Promotion activity. The induction of inflammation in skin mediated by TPA is believed to be governed by cyclooxygenase (COX), lipoxygenase and ornithine decarboxylase (ODC). These markers of inflammatory responses are important for skin Tumor Promotion. In our present study, we studied the chemopreventive effect of glycyrrhizin on TPA (20 nmol/0.2 mL acetone/animal, topically)-induced oxidative stress and hyperproliferation markers in skin. TPA enhanced lipid peroxidation with reduction in the level of catalase, glutathione, glutathione peroxidase, glutathione reductase and glutathione-s-transferase. TPA treatment also enhanced ODC activity and [3H] thym...
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attenuation of potassium bromate induced nephrotoxicity by coumarin 1 2 benzopyrone in wistar rats chemoprevention against free radical mediated renal oxidative stress and Tumor Promotion response
Redox Report, 2004Co-Authors: Naghma Khan, Sonia Sharma, Sarwat SultanaAbstract:We report the modulatory effect of coumarin (1,2-benzopyrone) on potassium bromate (KBrO(3)) mediated nephrotoxicity in Wistar rats. KBrO(3) (125 mg/kg body weight, i.p.) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H(2)O(2)) generation with reduction in renal glutathione content and antioxidant enzymes. It also enhances blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and [(3)H]-thymidine incorporation into renal DNA. Treatment of rats orally with coumarin (10 mg/kg body weight and 20 mg/kg body weight) resulted in a significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H(2)O(2) generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01) and antioxidant enzymes were also recovered to significant level (P < 0.001). These results show that coumarin may be used as an effective chemopreventive agent against KBrO(3)-mediated renal oxidative stress, toxicity and Tumor Promotion response in Wistar rats.
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inhibition of benzoyl peroxide and ultraviolet b radiation induced oxidative stress and Tumor Promotion markers by cycloartenol in murine skin
Redox Report, 2003Co-Authors: Sarwat Sultana, Naghma Khan, Aftab Alam, Sonia SharmaAbstract:AbstractThe chemopreventive potential of cycloartenol on benzoyl peroxide and UVB radiation-induced cutaneous Tumor Promotion markers and oxidative stress in murine skin is assessed. Benzoyl peroxide treatment (20 mg/animal/0.2 ml acetone) and UVB radiation (0.420 J/m2/s) caused a decrease in the activities of cutaneous antioxidant enzymes namely, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, phase II metabolizing enzyme such as glutathione-S-transferase and quinone reductase and depletion in the level of cutaneous glutathione. There was also enhancement in cutaneous microsomal lipid peroxidation, xanthine oxidase activity, [14C]-ornithine decarboxylase activity and [3H]-thymidine incorporation into cutaneous DNA. Cycloartenol was topically applied prior to the application of benzoyl peroxide at dose levels of 0.2 mg and 0.4 mg/kg body weight in acetone, which resulted in significant inhibition of epidermal ornithine decarboxylase activity and DNA synthesis (P...
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Modulation of biochemical parameters by Hemidesmus indicus in cumene hydroperoxide-induced murine skin: possible role in protection against free radicals-induced cutaneous oxidatve stress and Tumor Promotion
Journal of Ethnopharmacology, 2003Co-Authors: Sarwat Sultana, Naghma Khan, Sonia Sharma, Aftab AlamAbstract:Abstract Hemidesmus indicus has been shown to possess significant activity against immunotoxicity and other pharmacological and physiological disorders. In this communication, we have shown the modulating effect of H. indicus on cumene hydroperoxide-mediated cutaneous oxidative stress and Tumor Promotion response in murine skin. Cumene hydroperoxide treatment (30 mg per animal) increased cutaneous microsomal lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes and depletion in the level of glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes was observed. Cumene hydroperoxide treatment also induced the ornithine decarboxylase activity and enhanced the [ 3 H ]-thymidine uptake in DNA synthesis in murine skin. Application of ethanolic extract of H. indicus at a dose level of 1.5 and 3.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress, epidermal ornithine decarboxylase activity and enhanced DNA synthesis in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation and xanthine oxidase activity were significantly reduced (P
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chemopreventive effect of vitis vinifera extract on 12 o tetradecanoyl 13 phorbol acetate induced cutaneous oxidative stress and Tumor Promotion in murine skin
Pharmacological Research, 2002Co-Authors: Aftab Alam, Naghma Khan, Mohammad Saleem, Sonia Sharma, Sarwat SultanaAbstract:Abstract Vitis vinifera (grapes) is used as a fruit worldwide and known for its pharmacological properties. The present paper assesses the chemopreventive potential of Vitis vinifera against 12- O -tetradecanoyl-13-phorbol acetate (TPA)-mediated Tumor Promotion in 7,12-dimethyl-benz[a]anthracene (DMBA) initiated mice skin. Skin Tumor initiation was achieved by a single topical application of DMBA (40 μ g/animal/0.20 ml acetone) to mice. Two weeks after the initiation, promoting agent, TPA (5.0 μ g/animal/0.2 ml acetone) was applied two times a week for 20 weeks. Pretreatment of Vitis vinifera 1 h prior to each application of TPA resulted in protection against cutaneous Tumorigenesis in dose-dependent manner. This inhibition was evident when Tumor data was considered as the percentage of mice with Tumor and the number of Tumors per mouse. We have shown that typical application of Vitis vinifera prior to that of TPA resulted in significant inhibition against TPA-caused induction of epidermal ODC activity ( P Vitis vinifera at a dose level of 5.0 mg and 10.0 mg kg −1 body weight in acetone prior to that of TPA treatment resulted in partial significant inhibition of oxidative stress in dose-dependent manner. The concomitant increase in the microsomal lipid peroxidation and xanthine oxidase activities were significantly reduced ( P Vitis vinifera can be used as a chemopreventive agent against oxidative stress and carcinogenesis.
Hirota Fujiki - One of the best experts on this subject based on the ideXlab platform.
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discrete roles of cytokines tnf α il 1 il 6 in Tumor Promotion and cell transformation
International Journal of Oncology, 2002Co-Authors: Masami Suganuma, Sachiko Okabe, Miki Kurusu, Naoyuki Iida, Shiro Ohshima, Yukihiko Saeki, Tadamitsu Kishimoto, Hirota FujikiAbstract:Based on our previous results, which pointed to Tumor necrosis factor-alpha (TNF-alpha) as the essential cytokine in Tumor Promotion in mouse skin, we present here three principal findings related to the specific roles of TNF-alpha, interleukin-1 (IL-1) and IL-6 in Tumor Promotion (using TNF-alpha- and IL-6-deficient mice) and in BALB/3T3 cell transformation: i) The previously reported residual Tumor Promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in TNF-/- mice was confirmed by experiments with TNF+/+ and TNF-/- 129/Svj mice of the same strain, using two-stage carcinogenesis experiments. TPA produced Tumors in 100% of TNF+/+ and 78% of TNF-/- mice at 20 weeks, and the average number of Tumors per mouse was 11.1 in the former group and 2.1 in the latter. Judging from the expression of various inflammatory cytokine genes in TNF+/+ and TNF-/- mice, the residual Tumor promoting activity of TPA in TNF-/- mice may be dependent on expression of IL-1alpha and IL-1beta genes. ii) Tumor Promotion by TPA and okadaic acid in IL-6+/+ and IL-6-/- C57/BL6 mice was studied, with TPA producing Tumors in 57.1% of IL-6+/+ and 40.0% of IL-6-/- mice at 20 weeks, and okadaic acid in 40.0% of IL-6+/+ and 53.3% of IL-6-/- mice. Thus, there was no significant difference between TPA or okadaic acid Tumor Promotion in either group. In addition, expression of IL-6 gene in skin of both types of mice suggested that IL-6 is not the essential cytokine in Tumor Promotion, since it can be replaced by other cytokines. iii) In transformed clones of BALB/3T3 cells induced by TNF-alpha alone, IL-1alpha gene expression was induced after transformation by TNF-alpha had occurred, which did not occur in parental cells. Expression patterns of TNF-alpha, IL-1beta, IL-6 and IL-10, along with TGF-beta, were similar in both parental and transformed cells. Considering all these results, we conclude that various cytokines have discrete roles in Tumor Promotion and cell transformation.
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essential role of Tumor necrosis factor α tnf α in Tumor Promotion as revealed by tnf α deficient mice
Cancer Research, 1999Co-Authors: Masami Suganuma, Sachiko Okabe, Michael W Marino, Ayako Sakai, Eisaburo Sueoka, Hirota FujikiAbstract:To examine the hypothesis that Tumor necrosis factor (TNF) alpha is an essential cytokine in carcinogenesis, we conducted two-stage carcinogenesis experiments with an initiator, 7,12-dimethylbenz(a)anthracene (DMBA), plus either of two Tumor promoters, okadaic acid and 12-O-tetradecanoylphorbol-13-acetate (TPA), on the skin of TNF-alpha-deficient (TNF-/-) mice. TNF-/- mice treated with DMBA plus okadaic acid developed no Tumors for up to 19 weeks, and at 20 weeks, the percentage of Tumor-bearing TNF-/- mice was 10%, whereas the percentage of Tumor-bearing TNF+/+ mice was 100%. In TNF-/- mice treated with DMBA plus TPA, Tumor onset was delayed 4 weeks, and the time to development of small Tumors in 100% of mice was 9 weeks later than that seen in TNF+/+ CD-1 mice. The average number of Tumors in TPA-treated TNF-/- mice was 2.8, compared with 11.8 for TNF+/+ CD-1 mice. To understand the residual Tumor-promoting activity in TNF-/- mice, we also investigated the possible significance of interleukin (IL) 1 as an additional cytokine in Tumor Promotion. A single application of TPA and okadaic acid increased IL-1alpha and IL-1beta gene expression in TNF-/- mice. All of our results demonstrate that TNF-alpha is the key cytokine for Tumor Promotion in mouse skin and, very possibly, for carcinogenesis in humans as well.
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twist form of teleocidin derivatives is active in in vivo Tumor Promotion by benzolactam v8 310
Biological & Pharmaceutical Bulletin, 1998Co-Authors: Sachiko Okabe, Masami Suganuma, Yasuyuki Endo, Koichi Shudo, Naoko Sueoka, Atsumasa Komori, Hirota FujikiAbstract:: Teleocidin derivatives and the core structure, (-)-indolactam-V ((-)-IL-V), adopt two conformations in solution, the "twist" and the "sofa" forms. (-)-Benzolactam-V8-310 ((-)-BL-V8-310), which specifically adopts the twist form in solution, has been reported to have a significant effect on HL-60 cells and protein kinase C affinity. In this paper, we describe the biological activity with regard to Tumor Promotion on mouse skin and the wide variety of biological activity of (-)-BL-V8-310 and its derivatives. In both twist and sofa forms (-)-BL-V8-310 inhibited specific 3H-12-O-tetradecanoylphorbol-13-acetate (TPA) binding to a particulate fraction of mouse skin more strongly than (-)-IL-V. The doses for 50% inhibition (IC50) of (-)-IL-V, (-)-BL-V8-310, and teleocidin B-4 were 1000, 400 and 12 nM, respectively. As for the induction of Tumor necrosis factor-alpha (TNF-alpha) release into the medium from HL-60 cells, the EC200 values, which are the concentrations of the compound required to achieve 200 pg/ml TNF-alpha in the medium, were 1700, 500 and 19 nM for (-)-IL-V, (-)-BL-V8-310 and teleocidin B-4, respectively. The same amounts (5.5 nmol per application) of (-)-BL-V8-310 and teleocidin B-4, induced Tumors on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA) in 13.3% and 86.7% of Tumor-bearing mice, respectively, in week 20. These results confirmed that the twist form of teleocidin derivatives is the active form as far as the induction of biological activity is concerned. Also (-)-BL-V8-310 is a new synthetic Tumor promoter designed from data obtained using the receptor cavity model of TPA-type Tumor promoters.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and skin Tumor Promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to skin Tumor Promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall Promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to skin Tumor Promotion by diverse promoting stimuli.
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comparison of 12 o tetradecanoylphorbol 13 acetate and teleocidin for induction of epidermal hyperplasia activation of epidermal pkc isozymes and skin Tumor Promotion in sencar and c57bl 6 mice
Carcinogenesis, 1993Co-Authors: Akira Imamoto, Hirota Fujiki, Susan E Walker, Linda M Beltran, Xiao-jing Wang, John DigiovanniAbstract:: The present study compared the ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin to induce sustained epidermal hyperplasia, activate partially purified epidermal protein kinase C (PKC) isozymes and promote skin Tumors in SENCAR and C57BL/6 mice. Teleocidin was less effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, promoting skin Tumors and activating partially purified epidermal PKC isozymes in vitro when examined using SENCAR mice. In contrast, teleocidin was more effective than TPA on a molar basis for inducing sustained epidermal hyperplasia, approximately equi-effective for promoting skin Tumors and significantly less effective for activating PKC isozymes in vitro when examined using C57BL/6 mice. Despite the differences in response of C57BL/6 mice to TPA and teleocidin, this mouse strain was still highly resistant to skin Tumor Promotion by both types of promoters when compared with SENCAR mice. The current results, when considered in light of our recent studies (Cancer Res., 51, 1398-1405, 1991), indicate that C57BL/6 are generally resistant to a variety of classes of skin Tumor promoters, including the teleocidins. In addition, except for the phorbol esters, the induction of sustained epidermal hyperplasia does not appear to be as good a marker for overall Promotion responsiveness between SENCAR and C57BL/6 mice with other classes of Tumor promoters; although the induction of a significant sustained hyperplasia in the latter mouse strain did yield a weak Tumor response. Taken together, the current data suggest that factors in addition to the induction of sustained epidermal hyperplasia, control responsiveness of C57BL/6 mice to skin Tumor Promotion by diverse promoting stimuli.
Mohammad Saleem - One of the best experts on this subject based on the ideXlab platform.
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inhibition of 12 o tetradecanoylphorbol 13 acetate induced Tumor Promotion markers in cd 1 mouse skin by oleandrin
Toxicology and Applied Pharmacology, 2004Co-Authors: Farrukh Afaq, Mohammad Saleem, Moammir H Aziz, Hasan MukhtarAbstract:Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess anti-inflammatory and Tumor cell growth-inhibitory effects. Here, we provide evidence that oleandrin could possess anti-Tumor promoting effects. We determined the effect of topical application of oleandrin to CD-1 mice against l2-O-tetradecanoylphorbol-13-acetate (TPA), a widely studied skin Tumor promoter, -induced conventional and novel markers of skin Tumor Promotion. Topical application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse) application onto the skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in cutaneous edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX-2) protein expression. In search for novel markers of skin Tumor Promotion, we found that TPA application to mouse skin resulted, as an early event, in an increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical application of oleandrin before TPA application to mouse skin resulted in significant reduction in TPA-induced expression of PI3K and phosphorylation of Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic transcription factor that is critically involved in regulating the expression of specific genes that participate in inflammation, apoptosis and cell proliferation. Employing Western blot analysis, we found that oleandrin application to mouse skin resulted in inhibition of TPA-induced activation of NF-kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data suggest that oleandrin could be a useful anti-Tumor promoting agent because it inhibits several biomarkers of TPA-induced Tumor Promotion in an in vivo animal model. One might envision the use of chemopreventive agents such as oleandrin in an emollient or patch for chemoprevention or treatment of skin cancer.
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chemopreventive effect of vitis vinifera extract on 12 o tetradecanoyl 13 phorbol acetate induced cutaneous oxidative stress and Tumor Promotion in murine skin
Pharmacological Research, 2002Co-Authors: Aftab Alam, Naghma Khan, Mohammad Saleem, Sonia Sharma, Sarwat SultanaAbstract:Abstract Vitis vinifera (grapes) is used as a fruit worldwide and known for its pharmacological properties. The present paper assesses the chemopreventive potential of Vitis vinifera against 12- O -tetradecanoyl-13-phorbol acetate (TPA)-mediated Tumor Promotion in 7,12-dimethyl-benz[a]anthracene (DMBA) initiated mice skin. Skin Tumor initiation was achieved by a single topical application of DMBA (40 μ g/animal/0.20 ml acetone) to mice. Two weeks after the initiation, promoting agent, TPA (5.0 μ g/animal/0.2 ml acetone) was applied two times a week for 20 weeks. Pretreatment of Vitis vinifera 1 h prior to each application of TPA resulted in protection against cutaneous Tumorigenesis in dose-dependent manner. This inhibition was evident when Tumor data was considered as the percentage of mice with Tumor and the number of Tumors per mouse. We have shown that typical application of Vitis vinifera prior to that of TPA resulted in significant inhibition against TPA-caused induction of epidermal ODC activity ( P Vitis vinifera at a dose level of 5.0 mg and 10.0 mg kg −1 body weight in acetone prior to that of TPA treatment resulted in partial significant inhibition of oxidative stress in dose-dependent manner. The concomitant increase in the microsomal lipid peroxidation and xanthine oxidase activities were significantly reduced ( P Vitis vinifera can be used as a chemopreventive agent against oxidative stress and carcinogenesis.
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tephrosia purpurea alleviates phorbol ester induced Tumor Promotion response in murine skin
Pharmacological Research, 2001Co-Authors: Mohammad Saleem, Salahuddin Ahmed, Aftab Alam, Sarwat SultanaAbstract:Abstract In recent years, considerable emphasis has been placed on identifying new cancer chemopreventive agents, which could be useful for the human population. Tephrosia purpurea has been shown to possess significant activity against hepatotoxicity, pharmacological and physiological disorders. Earlier we showed that Tephrosia purpurea inhibits benzoyl peroxide-mediated cutaneous oxidative stress and toxicity. In the present study, we therefore assessed the effect of Tephrosia purpurea on 12-O-tetradecanoyl phorbal-13-acetate (TPA; a well-known phorbol ester) induced cutaneous oxidative stress and toxicity in murine skin. The pre-treatment of Swiss albino mice with Tephrosia purpurea prior to application of croton oil (phorbol ester) resulted in a dose-dependent inhibition of cutaneous carcinogenesis. Skin Tumor initiation was achieved by a single topical application of 7,12-dimethyl benz(a)anthracene (DMBA) (25 μ g per animal per 0.2 ml acetone) to mice. Ten days later Tumor Promotion was started by twice weekly topical application of croton oil (0.5% per animal per 0.2 ml acetone, v /v). Topical application of Tephrosia purpurea 1 h prior to each application of croton oil (phorbol ester) resulted in a significant protection against cutaneous carcinogenesis in a dose-dependent manner. The animals pre-treated with Tephrosia purpurea showed a decrease in both Tumor incidence and Tumor yield as compared to the croton oil (phorbol ester)-treated control group. In addition, a significant reduction in TPA-mediated induction in cutaneous ornithine decarboxylase (ODC) activity and [ 3 H]thymidine incorporation was also observed in animals pre-treated with a topical application of Tephrosia purpurea . The effect of topical application of Tephrosia purpurea on TPA-mediated depletion in the level of enzymatic and non-enzymatic molecules in skin was also evaluated and it was observed that topical application of Tephrosia purpurea prior to TPA resulted in the significant recovery of TPA-mediated depletion in the level of these molecules, namely glutathione, glutathione S-transferase, glutathione reductase and catalase. From these data we suggest that Tephrosia purpurea can abrogate the Tumor-promoting effect of croton oil (phorbol ester) in murine skin.
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lupeol a triterpene inhibits early responses of Tumor Promotion induced by benzoyl peroxide in murine skin
Pharmacological Research, 2001Co-Authors: Mohammad Saleem, Aftab Alam, Shamasul Arifin, Shafi M Shah, Bahar Ahmed, Sarwat SultanaAbstract:The modulating effect of Lupeol [lup-20(29)-en-3 β -ol], a triterpene found in many fruits and medicinal plants, on benzoyl peroxide-induced Tumor Promotion responses or Tumor Promotion in murine skin is described. Benzoyl peroxide is an effective cutaneous Tumor promoter acting through the generation of oxidative stress, the induction of ornithine decarboxylase activity and the enhancement of DNA synthesis. Benzoyl peroxide treatment increases cutaneous microsomal lipid peroxidation and hydrogen peroxide generation. The activity of the cutaneous antioxidant enzymes, namely catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase, is decreased and levels of cutaneous glutathione are depleted. Benzoyl peroxide treatment also induces ornithine decarboxylase activity and enhances [3H]thymidine uptake in DNA synthesis. Prophylactic treatment of mice with lupeol (0.75 and 1.5 mg per animal) 1 hour before benzoyl peroxide treatment resulted in a diminution of benzoyl peroxide-mediated damage. The susceptibility of cutaneous microsomal membrane to lipid peroxidation and hydrogen peroxide generation was significantly reduced (P< 0.01 and P< 0.01, respectively). In addition, depleted levels of glutathione and inhibited activity of antioxidant enzymes were recovered to a significant level (P< 0.01, P< 0.05 and P< 0.01, respectively). Similarly, the elevated ornithine decarboxylase activity and enhanced thymidine uptake in DNA synthesis were inhibited significantly (P< 0.05) in a dose-dependent manner. The protective effect of lupeol was dose dependent in all parameters. The results suggest that lupeol is an effective skin chemopreventive agent that may suppress benzoyl peroxide-induced cutaneous toxicity.
Hasan Mukhtar - One of the best experts on this subject based on the ideXlab platform.
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inhibition of 12 o tetradecanoylphorbol 13 acetate induced Tumor Promotion markers in cd 1 mouse skin by oleandrin
Toxicology and Applied Pharmacology, 2004Co-Authors: Farrukh Afaq, Mohammad Saleem, Moammir H Aziz, Hasan MukhtarAbstract:Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess anti-inflammatory and Tumor cell growth-inhibitory effects. Here, we provide evidence that oleandrin could possess anti-Tumor promoting effects. We determined the effect of topical application of oleandrin to CD-1 mice against l2-O-tetradecanoylphorbol-13-acetate (TPA), a widely studied skin Tumor promoter, -induced conventional and novel markers of skin Tumor Promotion. Topical application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse) application onto the skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in cutaneous edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX-2) protein expression. In search for novel markers of skin Tumor Promotion, we found that TPA application to mouse skin resulted, as an early event, in an increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical application of oleandrin before TPA application to mouse skin resulted in significant reduction in TPA-induced expression of PI3K and phosphorylation of Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic transcription factor that is critically involved in regulating the expression of specific genes that participate in inflammation, apoptosis and cell proliferation. Employing Western blot analysis, we found that oleandrin application to mouse skin resulted in inhibition of TPA-induced activation of NF-kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data suggest that oleandrin could be a useful anti-Tumor promoting agent because it inhibits several biomarkers of TPA-induced Tumor Promotion in an in vivo animal model. One might envision the use of chemopreventive agents such as oleandrin in an emollient or patch for chemoprevention or treatment of skin cancer.
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inhibition of Tumor Promotion in sencar mouse skin by ethanol extract of zingiber officinale rhizome
Cancer Research, 1996Co-Authors: Santosh K Katiyar, Rajesh Agarwal, Hasan MukhtarAbstract:There is considerable emphasis on identifying potential chemopreventive agents present in food consumed by the human population. Ginger rhizome (Zingiber officinale), known commonly as ginger, is consumed worldwide in cookeries as a spice and a flavoring agent. In prior in vitro studies, it has been shown that the water or organic solvent extract of ginger possesses antioxidative and antiinflammatory properties. In this study, we evaluated whether ethanol extract of ginger (GE) possesses anti-Tumor-promoting effects in a mouse skin Tumorigenesis model. Because skin Tumor promoters induced epidermal ornithine decarboxylase (ODC), cyclooxygenase, and lipoxygenase activities, and edema and hyperplasia are conventionally used markers of skin Tumor Promotion, first, we assessed the effect of GE on these parameters. Preapplication of GE onto the skin of SENCAR mice resulted in significant inhibition of 12-0-tetradecanoylphorbol-13-acetate (TPA)-caused induction of epidermal ODC, cyclooxygenase, and lipoxygenase activities and ODC mRNA expression in a does-dependent manner. Preapplication of GE to mouse skin also afforded significant inhibition of TPA-caused epidermal edema (56%) and hyperplasia (44%). In long-term Tumor studies, topical application of GE 30 min prior to that of each TPA application to 7,12-dimethylbenz(a)anthracene-initiated SENCAR mice resulted in a highly significant protection against skin Tumor incidence and its subsequent multiplicity. The animals pretreated with GE showed substantially lower Tumor body burdens compared with non-GE-treated controls. The results of our study, for the first time, provide clear evidence that GE possesses anti-skin Tumor-promoting effects, and that the mechanism of such effects may involve inhibition of Tumor promoter-caused cellular, biochemical, and molecular changes in mouse skin.
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inhibition of 12 o tetradecanoylphorbol 13 acetate caused Tumor Promotion in 7 12 dimethylbenz a anthracene initiated sencar mouse skin by a polyphenolic fraction isolated from green tea
Cancer Research, 1992Co-Authors: Santosh K Katiyar, Rajesh Agarwal, Gary S Wood, Hasan MukhtarAbstract:Our laboratory has been studying cancer chemopreventive effects of polyphenolic fraction isolated from green tea (GTP). In prior studies we have shown that (a) GTP possesses antigenotoxic effects in various test systems; (b) topical application of GTP protects against UV radiation and chemical carcinogen-induced Tumorigenesis in murine skin; and (c) feeding of GTP in drinking water p.o. to mice protects against carcinogen-induced forestomach and lung Tumorigenesis. Recently, we showed that in a dose-dependent manner GTP inhibits Tumor promoter-caused induction of epidermal ornithine decarboxylase activity in SENCAR mice (R. Agarwal et al., Cancer Res., 52: 3582-3588, 1992). In the present study, we assessed the effect of GTP on TPA-induced skin Tumor Promotion in 7,12-dimethylbenz(a)anthracene-initiated SENCAR mouse. Topical application of varying doses of GTP (1-24 mg) 30 min prior to that of each TPA application resulted in highly significant protection against skin Tumor Promotion in a dose-dependent manner. The animals pretreated with GTP showed substantially lower Tumor body burden such as decrease in total number of Tumors per group, number of Tumors per animal, Tumor volume per mouse, and average volume per Tumor, as compared to the animals that did not receive GTP. Since TPA-induced epidermal cyclooxygenase and lipoxygenase activities and edema and hyperplasia are conventionally used markers of skin Tumor Promotion, we also assessed the effect of preapplication of GTP on these parameters. As quantitated by the formation of prostaglandin and hydroxy-eicosatetraenoic acid metabolites from, respectively, cyclooxygenase- and lipoxygenase-catalyzed metabolism of arachidonic acid, skin application of GTP to SENCAR mice resulted in significant inhibition of TPA-caused effects on these 2 enzymes. Prior application of GTP to mouse skin also resulted in 30-46% inhibition of TPA-induced epidermal edema and hyperplasia. The results of the present study suggest that GTP possesses anti-skin Tumor-promoting effects, and that the mechanism of such effects may involve inhibition of Tumor promoter-induced epidermal ornithine decarboxylase, cyclooxygenase and lipoxygenase activities, edema, and hyperplasia. Further studies are in progress to define which component present in GTP is responsible for its anti-skin Tumor-promoting effects.
