Inhibition of DMBA-croton Oil Two-stage Mouse Skin Carcinogenesis by Diphenylmethyl Selenocyanate Through Modulation of Cutaneous Oxidative Stress and Inhibition of Nitric Oxide Production

Selenium, an essential micronutrient, plays important roles against different diseases, including several types of ‍cancer. In the present study, antioxidative and chemopreventive properties of a synthetic organoselenium compound, ‍diphenylmethyl selenocyanate, were evaluated with a 7,12-dimethylbenz (a) anthracene - croton oil induced twostage ‍mouse skin carcinogenesis model. ‍The compound was administered orally to carcinogen-treated mice at two different non-toxic doses, 2mg/kg. ‍b.w. and 3mg/kg. b.w. Significant inhibition in the incidence of papilloma formation (53-80%) as well as in the ‍cumulative numbers of papillomas per papilloma bearing mouse were observed in the treated groups as compared ‍to the carcinogen control group. The compound was also found to upregulate significantly different phase II detoxifying ‍enzymes such as glutathione-S-transferase (p<0.01) and superoxide dismutase (p<0.01) in skin cytosol when measured ‍after 15 days and also after 12 weeks of the first 7,12-dimethylbenz (a) anthracene treatment. Lipid peroxidation ‍measured with reference to thiobarbituric acid reactive substances in skin microsomes was significantly inhibited ‍(p<0.05) in a dose dependent manner by diphenylmethyl selenocyanate. Considerable inhibition of the level of nitric ‍oxide production in peritoneal macrophages was observed after 12 weeks (p<0.05). ‍Thus the compound appears to exert chemopreventive activity in terms of papilloma formation, which may be ‍through modulation of cutaneous lipid peroxidation, the phase II detoxifying enzyme system and nitric oxide ‍production.     

Saffron Can Prevent Chemically Induced Murine Skin Carcinogensis In Swiss Albino Mice

One of the most promising strategies for cancer prevention today is chemoprevention using readily available ‍natural substances from vegetables, fruits, herbs and spices . Among the spices, saffron (Crocus sativus, L) a member ‍of the large family Iridaceae, has drawn attention because apart from its use as a flavouring agent, pharmacological ‍studies have demonstrated many health promoting properties including radical scavenging, anti- mutagenic and ‍immuno-modulating effects. In the present study the effects of an aqueous infusion of saffron on two stage skin ‍papillogenesis / carcinogenesis in mice initiated by 7-12 dimethyl benz[a] anthracin (DMBA) and promoted with ‍croton oil were investigated. Significant reduction in papilloma formation was found with saffron application in the ‍pre-initation and post-initation periods, and particular when the agent was given both pre- and post-initation. The ‍inhibition appeared to be at least partly due on modulatory effects of saffron on some phase II detoxifying enzymes ‍like glutathione-S-transferase (GST) and glutahinoe peroxidase (GPx), as well as catalase (CAT) and superoxide ‍dismutase (SOD). ‍     

Chemomodulatory Effect of Moringa Oleifera,Lam, on Hepatic Carcinogen Metabolising Enzymes,Antioxidant Parameters and Skin Papillomagenesis in Mice

The modulatory effects of a hydro-alchoholic extract of drumsticks of Moringa oliefera Lam at doses of 125 mg/ ‍kg bodyweight and 250 mg/ kg body weight for 7 and 14 days, respectively, were investigated with reference to drug ‍metabolising Phase I (Cytochrome b5 and Cytochrome P450 ) and Phase II (Glutathione-S- transferase) enzymes, ‍anti-oxidant enzymes, glutathione content and lipid peroxidation in the liver of 6-8 week old female Swiss albino ‍mice. Further, the chemopreventive efficacy of the extract was evaluated in a two stage model of 7,12 – ‍dimethylbenz(a)anthracene induced skin papillomagenesis. Significant increase (p<0.05 to p<0.01) in the activities ‍of hepatic cytochrome b5, cytochrome P450, catalase, glutathione peroxidase ( GPx ), glutathione reductase (GR), acid ‍soluble sulfhydryl content (-SH ) and a significant decrease ( p<0.01 ) in the hepatic MDA level were observed at ‍both dose levels of treatment when compared with the control values. Glutathione-S- transferase ( GST )activity was ‍found to be significantly incr eased (p<0.01 ) only at the higher dose level. Butylated hydr oxyanisol (BHA ) fed at a ‍dose of 0.75% in the diet for 7 and 14 days (positive control ) caused a significant increase (p<0.05 to p<0.01) in the ‍levels of hepatic phase I and phase II enzymes, anti- oxidant enzymes, glutathione content and a decrease in lipid ‍peroxidation. The skin papillomagenesis studies demonstrated a significant decrease (p<0.05 ) in the percentage of ‍mice with papillomas, average number of papillomas per mouse and papillomas per papilloma bearing mouse when ‍the animals received a topical application of the extract at a dose of 5mg/ kg body weight in the peri-initiation phase ‍7 days before and 7 days after DMBA application, Group II ), promotional phase (from the day of croton oil application ‍and continued till the end of the experiment, Group III ) and both peri and post initiation stages (from 7 days prior ‍to DMBA application and continued till the end of the experiment, Group IV) compared to the control group (Group ‍I ). The percentage inhibition of tumor multiplicity has been recorded to be 27, 72, and 81 in Groups II, III, and IV, ‍respectively. These findings are suggestive of a possible chemopreventive potential of Moringa oliefera drumstick ‍extract against chemical carcinogenesis.     

Anti-tumour Promoting Activity of Diphenylmethyl Selenocyanate Against Two-stage Mouse Skin Carcinogenesis

Epidemiological, clinical and experimental evidence collectively suggests that Se in different inorganic and organic ‍forms provides a potential cancer chemopreventive agent, active against several types of cancer. It can exert preventive ‍activity in all the three stages of cancer: initiation, promotion and progression. Literature reports revealed that ‍organoselenocyanates have more potential as chemopreventive agents than inorganic forms due to their lower toxicity. ‍In our previous report we showed chemopreventive efficacy of diphenylmethyl selenocyanate during the initiation ‍and pre- plus post-initiation phases of skin and colon carcinogenesis process. The present study was undertaken to ‍explore the anti-tumour promoting activity of diphenylmethyl selenocyanate in a 7,12-dimethylbenz (a) anthracene ‍(DMBA)-croton oil two-stage skin carcinogenesis model. The results obtained showed significant (p<0.01) reduction ‍of the incidence and number of skin papillomas, precancerous skin lesions, along with significant (p<0.01) elevation ‍of phase II detoxifying enzymes (GST, Catalase and SOD) and inhibition of lipid peroxidation in liver and skin. ‍Thus, the present data strongly suggest that diphenylmethyl selenocyanate also has the potential to act as antitumour ‍promoter agent in a two-stage skin carcinogenesis mouse model, pointing to possible general efficacy.     

Dietary Cardamom Inhibits the Formation of Azoxymethaneinduced Aberrant Crypt Foci in Mice and Reduces COX-2 and iNOS Expression in the Colon

Recently, considerable attention has been focused on identifying naturally occurring chemopreventive compounds ‍capable of inhibiting, retarding, or reversing the multi-step carcinogenesis. The primary aim of the present study ‍was to identify the effects of a commonly consumed spice, viz., cardamom against azoxymethane (AOM) induced ‍colonic aberrant crypt foci (ACF) in Swiss Albino mice. The secondary aim, was to explore the ability of cardamom ‍to modulate the status of proliferation and apoptosis, and to understand its role in altering cyclooxygenase-2 (COX- ‍2) and inducible nitric oxide synthase (iNOS) expression. Male Swiss albino mice were injected with AOM (dose: ‍5mg/Kg body weight) or saline (Group 1) weekly once for two weeks. The AOM-injected mice were randomly assigned ‍to two groups (Groups 2 and 3). While all the groups were on standard lab chow, Group 3 received oral doses of ‍0.5% cardamom, in aqueous suspension, daily for 8 weeks. Following treatment, significant reduction in the incidences ‍of aberrant crypt foci (p<0.05) was observed. This reduction in ACF was accompanied by suppression of cell ‍proliferation (mean Brdu LI in carcinogen control=13.91+3.31, and 0.5%cardamom=2.723+0.830) and induction of ‍apoptosis (mean AI in carcinogen control=1.547+0.42 and 0.5% cardamom= 6.61+0.55). Moreover, reduction of ‍both COX-2 and iNOS expression was also observed. These results suggest that aqueous suspensions of cardamom ‍have protective effects on experimentally induced colon carcinogenesis. Cardamom as a whole and its active ‍components require further attention if the use of this spice is to be recommended for cancer prevention.     

Oral Consumption of Bitter Gourd and Tomato Prevents Lipid Peroxidation in Liver During Skin Carcinogenesis in Mice

The protective role of two commonly consumed natural dietary items- bitter gourd and tomato against endogenous ‍as well as 7,12- dimethylbenz(a)anthracene (DMBA) induced lipid peroxidation in the livers of mice was investigated. ‍The rationale for such an approach is that lipid peroxidation has been suggested to play a key role in human cancer ‍development. There was a sharp rise in lipid peroxidation (measured as thiobarbituric acid reactive substances ‍formation) during skin carcinogenesis induced by DMBA in mice. Aqueous extracts of bitter gourd and tomato juice ‍were found to be very potent inhibitors of lipid peroxidation both in normal and DMBA treated mice. Our observations ‍support the hypothesis that natural combinations of phytochemicals present in the fruit juices exert cancer-protective ‍effects via a decrease in lipid peroxidation.     

Targeting Angiogenesis – a Novel Mode in Cancer Chemoprevention

Cancer prevention is fast emerging as a discipline with a promising potential. Chemoprevention has its rationale ‍in the multistage process of carcinogenesis which provides an option for development of preventive approaches in ‍the early, premalignant stages, before appearance of clinical symptoms. Evidence is mounting that the angiogenic ‍switch may be an early event in carcinogenesis. Most chemopreventive agents currently under development probably ‍act via multiple mechanisms. The chemopreventives used in clinical trials, such as nonsteroidal anti-inflammatories, ‍tamoxifen and retinoids, have been shown to inhibit angiogenesis, the formation of new vessels from existing ‍vasculature, which may contribute to their protective effect. Development and use, alone or in combination with ‍other agents with other mechanisms of action, of specific antiangiogenic agents is likely to open new possibilities in ‍cancer chemoprevention. ‍     

Indian Food Ingredients and Cancer Prevention - an Experimental Evaluation of Anticarcinogenic Effects of Garlic in Rat Colon

The major food items of Indian cuisine include rice, wheat, diary products, and abundant fruits and vegetables. ‍Beside these, there are several kinds of herbs and spices as important ingredients, containing many phytochemicals ‍with medicinal properties, adding taste to Indian cuisine. An impressive body of data exists in support of the concept ‍that Indian food ingredients can be used in preventive strategies aimed at reducing the incidence and mortality of ‍different types of cancers because of their antioxidative, antimutagenic and anticarcinogenic properties. Vital ‍ingredients used in Indian cooking include turmeric, cloves, ginger, aniseed, mustard, saffron, cardamom and garlic ‍Garlic is an indispensable ingredient of Indian food and this report concerns the chemopreventive efficacy of garlic ‍in an azoxymethane induced rodent colon carcinogenesis model. The effect of garlic was evaluated in terms of aberrant ‍crypt foci, putative preneoplastic lesions in the colon. In addition, cell proliferation and levels of apoptosis were ‍determined and the expression of cyclooxygenase-2 protein was analyzed. Following treatment, significant inhibition ‍of cell proliferation and induction of apoptosis, as well as suppression of cyclooxygenase-2 activity were observed, ‍associated with significant reduction in the incidence of aberrant crypt foci. The study points to combined protective ‍effects of garlic components on colon carcinogenesis. ‍     

Phellinus rimosus (Berk.) pilat attenuates 7,12-dimethylbenz[a] anthracene induced and croton oil promoted skin papilloma formation in mice

The roles of 7,12-dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), and 12-O-tetradecanoylphorbol-13-acetate (TPA) a skin tumor promoter present in croton oil, are clearly implicated in the formation of skin papilloma. The effect of ethyl acetate extract of Phellinus rimosus, a polypore macro fungus, against croton oil-induced skin inflammation, lipid peroxidation and tumor promotion was studied. The antiinflammatory and lipid peroxidation inhibiting activities were determined by topical application of extract of P. rimosus (10 and 20 mg) prior to the application of 0.1 ml of 50% croton oil in acetone. The tumor promotion inhibiting effect of P. rimosus was evaluated against DMBA-initiated, croton oil promoted two-stage carcinogenesis model in mouse skin. The results showed that topical application of the extract (10 and 20 mg) significantly (p < 0.01) and dose dependently attenuate the inflammatory edema as well as lipid peroxidation induced by croton oil. Similarly, topical application of extract (1 and 5 mg) effectively ameliorated the croton oil promoted skin papilloma formation. The results of this study concluded that ethyl acetate extract of P. rimosus showed antitumor activity against DMBA initiated, croton oil promoted skin papilloma formation which can be partially ascribed to the antiperoxidative and anti-inflammatory effects of the extract.     

Lack of Carcinogenic Sensitivity of the Glandular Stomach in Heterozygous p53 Knockout Mice Given N-Methyl-N-Nitrosourea in their Drinking Water for 26 Weeks

Gastric tumorigenic sensitivity to N-methyl-N-nitrosourea (MNU) was examined in heterozygous p53 knockout ‍(p53(+/-)) CBA mice and their wild-type littermates (p53(+/+)). In Experiment 1, 37 male p53(+/-) or 38 male p53(+/ ‍+) CBA mice were given MNU in their drinking water at concentration of 50ppm (Group 1 or 4), 10ppm (group 2 or ‍5) or 0ppm (group3 or 6) for 26 weeks. In Experiment 2, p53(+/-) and p53(+/+) CBA mice of both sexes received ‍water containing 50ppm MNU for 26 weeks. In Experiment 1, the incidences of hyperplasias in the glandular ‍stomach observed in p53 (+/-) CBA mice treated with 50ppm and 10ppm MNU were significantly increased, as ‍compared with the control group. No tumors were induced in the stomach of any treated groups. Some proliferative ‍or non-neoplastic lesions were observed in some p53 (+/-) CBA mice, but there was no significant difference in their ‍incidences between treated and control groups. In Experiment 2, the incidences of hyperplasias in the glandular ‍stomach observed in p53 (+/-) CBA mice of both sexes treated with 50ppm MNU were not significantly increased, as ‍compared with the treated p53(+/+) CBA group. One papilloma of the forestomach was observed only in a male ‍p53(+/-) CBA mouse treated with 50ppm MNU. The present study suggests that p53 (+/-) CBA mice have low ‍susceptibility to MNU-induced gastic carcinogenesis.     

Induction of murine fibrosarcomas by low dose treatment with 3-methylcholanthrene followed by promotion with 12-O-tetradecanoyl-phorbol-13-acetate

Repeated application of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA) to the skin of mice previously treated with an initiating dose of the carcinogen 7,12-dimethylbenz[a] anthracene has been shown to lead to an increased incidence of papilloma. The studies presented here describe a modified murine two-stage carcinogenesis model in which a single subcutaneous administration of the carcinogen 3-methylcholanthrene (3-MC) is followed by multiple applications of TPA administered subcutaneously or intraperitoneally. TPA was observed to act as a promoter under these conditions when given either subcutaneously or intraperitoneally. When a carcinogenic dose of 3-MC was administered (0.5 mg/mouse) followed by regular treatment with TPA (10 micrograms/mouse) the percent of tumor-bearing mice increased and the length of time until tumors developed significantly shortened. At a subcarcinogenic dose of 3-MC (0.025 mg/mouse), repeated treatment with TPA led to tumor development whereas no tumors were observed in mice not treated with TPA. All tumors were found to be fibrosarcomas. Thus, TPA is capable of acting as a systemic promoter of mesenchymally derived tumors.     

Chemopreventive Action of Emblica Officinalis on Skin Carcinogenesis in Mice

Chemoprevention with food phytochemicals is currently regarded as one of the most important strategies for ‍cancer control. Emblica officinalis (Family: Euphorbiaceae) indigenous to India, is valued for its unique tannins and ‍flavanoids, which contain very powerful antioxidant properties. The inhibition of tumor incidences by fruit extract ‍of this plant has been evaluated on two-stage process of skin carcinogenesis in Swiss albino mice, induced by a single ‍application of 7, 12-dimethyabenz(a)anthrecene (100 ìg/ 100 ìl acetone), and two weeks later, promoted by repeated ‍application of croton oil (1% in acetone/thrice a week) till the end of the experiment (16 weeks). The tumor incidence, ‍tumor yield, tumor burdon and cumulative number of papillomas were found to be higher in the control (without ‍EO treatment) as compared to experimental animals (EO treated). The differences in the values of the results of ‍experimental groups were statistically analysed and found to be significant in comparison to the control group (p< ‍0.05). The present study demonstrates the chemopreventive potential of Emblica officinalis fruit extract on DMBA ‍induced skin tumorigenesis in Swiss albino mice. ‍     

Effects of dietary retinoic acid on skin papilloma and carcinoma formation in female SENCAR mice

Previously we have shown that dietary retinoids are essentialfor papilloma formation induced by either an initiation-promotionor a complete skin carcinogenesis protocol. The present studywas conducted to further determine the effect of dietary retinoicacid (RA) on papilloma formation and the conversion of papillomasto carcinomas. Skin tumors were induced in 3 week old femaleSENCAR mice by an initiation-promotion protocol with one applicationof 20 µg of 7,12-dimethylbenz[a]anthracene (DMBA), followedby 20 weekly applications of 2 µg of 12-O-tetradecanoylphorbol-13-acetate(TPA). Mice were fed RA at one of the three doses: 0.3 (nutritionallymarginal dose), 3 (near physiological) and 30 (pharmacological)µg/g of diet. Mice fed 30 µg of RA/g of diet hadthe same survival rate as the other two groups despite a lowerbody weight and all three groups had similar papilloma incidence,which reached 100% at age 18 weeks. Mice fed 3 µg of RA/gof diet had the highest papilloma yield (     

Inhibitory Effects of Heated Garlic on N-Ethyl-Nี-nitro-N-nitrosoguanidine-induced Carcinogenesis in the Duodenum and Jejunum of C57BL/6 Mice

We examined the modifying effects of heated garlic (Allium sativum L.) on N-ethyl-N’-nitro-N-nitrosoguanidine ‍(ENNG)-induced duodenal and jejunal carcinogenesis in mice. Heated garlic powder used in this study was prepared ‍as follows: unpeeled garlic bulbs were blanched in boiling water for 6 min, and then peeled, the cloves being crushed, ‍homogenized, and finally freeze-dried. The garlic powder had almost undetectable alliinase activity and was rich in ‍alliin (the main sulfur compound of heated garlic; 22.1 mg/g dry weight). Male C57BL/6 mice were given ENNG ‍(100 mg/l) in drinking water for the first 4 weeks, and then basal diet (Group 1), or 10% (Group 2), 3% (Group 3) or ‍1% (Group 4) heated garlic in the diet for 30 weeks. At the termination of the experiment, the incidences of duodenal ‍tumors in Groups 1-3 were significantly lower than those in Group 1, and the multiplicities in Group 2 were significantly ‍lower than those in Group 1. Additionally, the incidences and/or multiplicities of the jejunal tumors in Groups 2 and ‍4 were also significantly lower than those in Group 1. In this study, we also examined changes in erythrocyte polyamine ‍levels. Values for Group 1 were significantly greater than those in the control group, and this elevation in Group 1 ‍were significantly inhibited by dietary heated garlic (10% in the diet; Group 2). These results indicated that the ‍post-initiation-stage feeding of heated garlic, especially at 10% in the diet, inhibits ENNG-induced duodenal and ‍jejunal carcinogenesis in mice.     

Increased skin carcinogenesis in a keratinocyte directed thioredoxin-1 transgenic mouse

Thioredoxin-1 is a low molecular weight redox protein that protects cells against oxidant damage. Thioredoxin-1 levels are increased in the epidermal layer of sun-damaged human skin. Thioredoxin-1 levels are also increased in several human primary tumors where its expression is associated with increased tumor cell proliferation, decreased apoptosis and aggressive tumor growth. We have investigated whether increased thioredoxin-1 levels in skin can lead to increased tumor formation using transgenic mice with mouse thioredoxin-1 expressed in keratinocytes under the control of the keratinocyte-14 (K14) promoter. Thioredoxin-1 protein expression was increased 2-fold in the keratinocyte layer of the transgenic mice. The skin was macroscopically and histologically normal but in the two-stage model of carcinogenesis using topical dimethylbenzanthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 6-fold increase in the number of papillomas per mouse and a 3-fold increase in papilloma size in the K14 thioredoxin-1 transgenic mice compared with non-transgenic littermates. Thus, increased thioredoxin-1 in keratinocytes acts as an enhancer of carcinogenesis in the DMBA/TPA two-stage model of skin carcinogenesis in mice.     

白藜芦醇对癌的化学预防作用

背景与目的：白藜芦醇广泛存在于药食两用植物中,其开发利用已得到越来越多的关注。本研究旨在依据癌发生、发展的多阶段理论,选用经典的动物模型,从多个靶点探讨白藜芦醇对癌的化学预防作用。方法：采用抗Ames法、抗微核法检测白藜芦醇抗突变作用。巴豆油诱发的小鼠耳肿胀和小鼠表皮组织中鸟氨酸脱羧酶的活性来判断其抗促癌作用。通过检测二甲基苯蒽／巴豆油诱发的小鼠皮肤二阶段乳头状瘤模型全面观察其对肿瘤发生的抑制作用。结果：白藜芦醇可以明显减少致癌剂诱发的鼠伤寒沙门氏菌TA100回复突变菌落数,每皿用量100μg对甲基磺酸甲酯作用的抑制率达42．2％,每皿200μg对苯并芘作用的抑制率达91．8％。提前灌喂白藜芦醇可以显著对抗环磷酰胺诱发的小鼠骨髓嗜多染红细胞微核增加,并呈现较好的剂量依赖关系。将白藜芦醇以每日30mg／kg剂量灌喂6天,能有效减轻致炎剂引起的小鼠耳部急性炎性反应。以每日180mg／kg剂量给药3天,对巴豆油激发的小鼠表皮组织鸟氨酸脱羧酶活性增高抑制率达69．3％。应用白藜芦醇可以推迟二甲基苯蒽／巴豆油诱发的小鼠皮肤乳头状瘤发生时间,降低肿瘤发生率,减少平均荷瘤数。结论：白藜芦醇在癌发生的突变、促癌及演进各阶段均可发挥积极的对抗作用。作为癌化学预防剂,具有较好的开发应用前景。     

Genetic analyses of mouse skin tumor progression susceptibility using SENCAR inbred derived strains

Susceptibility to tumor development varies among individuals in the human population. This variability can also be found among different strains of mice, particularly in the mouse skin chemical carcinogenesis model. The genetic mechanisms underlying mouse skin tumor susceptibility are not fully understood. The SENCAR stock has been found to be the most sensitive mice for skin carcinogenesis studies; however, little is known about the genes underlying tumor susceptibility, particularly, those involved in tumor progression. Experiments with the SSIN/Sprd mice, an inbred strain derived from the outbred SENCAR stock, suggested that papilloma development, tumor promotion, and their conversion into squamous cell carcinomas (SCCs), progression, are regulated by different genes. In the highly sensitive SSIN/Sprd mice, papillomas rarely progress to SCC. Using crosses between the outbred SENCAR and the SSIN/Sprd mice, we previously determined that papilloma progression in the SENCAR stock could be controlled by at least one autosomal dominant gene. However, the outbred nature of the SENCAR stock precluded us from extending those findings. More recently, another inbred strain was developed from the outbred SENCAR stock, the SENCARB/Pt. These mice have similar tumor promotion sensitivity to the SSIN/Sprd but in contrast, have high papilloma progression susceptibility, similar to the outbred original stock. In the present study, we generated F(1), F(2), and backcross hybrids between the SSIN/Sprd and SENCARB/Pt mice to determine a possible model for tumor progression susceptibility and to map the putative tumor susceptibility genes. Our tumor data suggests that papilloma progression susceptibility in the SENCAR mouse skin model could be genetically determined by one susceptibility gene. Our preliminary linkage analysis failed to identify one strong susceptibility locus to confirm this but provided some evidence for at least one possible susceptibility locus in mouse chromosome 14.     

Quinone Reductase Inducers in Azadirachta indica A. Juss Flowers,and their Mechanisms of Action

We have previously shown that the flowers of neem tree (Azadirachta indica A. Juss, family Meliaceae), Thai ‍variety, strongly induced the activity of glutathione S-transferase (GST) while resulting in a significant reduction in ‍the activities of some cytochrome P450-dependent monooxygenases in rat liver, and possess cancer chemopreventive ‍potential against chemically-induced mammary gland and liver carcinogenesis in rats. In the present study, 2 ‍chemicals possessing strong QR inducing activity were fractionated from neem flowers using a bioassay based on ‍the induction of QR activity in mouse hepatoma Hepa 1c1c7 cultured cells. Spectroscopic characteristics revealed ‍that these compounds were nimbolide and chlorophylls, having CD (concentration required to double QR specific ‍activity) values of 0.16 and 3.8 ìg/ml, respectively. Nimbolide is a known constituent of neem leaves, but was found ‍for the first time here in the flowers. Both nimbolide and chlorophylls strongly enhanced the level of QR mRNA in ‍Hepa 1c1c7 cells, as monitored by northern blot hybridization, indicating that the mechanism by which these ‍constituents of neem flowers induced QR activity is the induction of QR gene expression. These findings may have ‍implication on cancer chemopreventive potential of neem flowers in experimental rats previously reported.     

Lack of effect of 94 GHz radio frequency radiation exposure in an animal model of skin carcinogenesis

Although there is no evidence that electromagnetic energy in the radio frequency radiation (RFR) band is mutagenic, there have been suggestions that RFR energy might serve as either a promoter or co-promoter in some animal models of carcinogenesis. Recent developments in electromagnetic technology have resulted in the manufacture of RFR sources capable of generating frequencies in the millimeter wavelength (MMW) range (30-300 GHz). Because absorption of MMW energy occurs in the skin, it is to be expected that long-term detrimental health effects, if any, would most likely be manifest in the skin. In this study we investigated whether a single (1.0 W/cm(2) for 10 s) or repeated (2 exposures/week for 12 weeks, 333 mW/cm(2) for 10 s) exposure to 94 GHz RFR serves as a promoter or co-promoter in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced SENCAR mouse model of skin carcinogenesis. Neither paradigm of MMW exposure significantly affected papilloma development, as evidenced by a lack of effect on tumor incidence and multiplicity. There was also no evidence that MMW exposure served as a co-promoter in DMBA-induced animals repeatedly treated with 12-O-tetradecanoylphorbol 13-acetate. Therefore, we conclude that exposure to 94 GHz RFR under these conditions does not promote or co-promote papilloma development in this animal model of skin carcinogenesis.     

An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

The levels of 8S-lipoxygenase (8S-LOX) expression and of its arachidonic acid metabolite, 8-hydroxyeicosatetraenoic acid (8-HETE), are highly elevated in the early stages of mouse skin carcinogenesis. On the other hand, several reports showing that 8-HETE is also closely associated with keratinocyte differentiation raise a question concerning the role of 8S-LOX/8-HETE in skin carcinogenesis. To address that question, here we conducted a series of gain-of-function studies. Skin targeted loricrin 8S-LOX/C57BL/6J transgenic mice showed a more differentiated epidermal phenotype as well as a 64% reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of 8S-LOX in MT1/2 cells, a murine papilloma cell line, also caused a more differentiated appearance as well as keratin 1 expression. Overexpression of 8S-LOX in CH72 cells, a murine carcinoma cell line, inhibited cell proliferation by 30% in vitro and by 86% in in vivo xenografts. Exogenous addition of 5 muM 8-HETE to CH72 cells caused cell cycle arrest at the G1 phase. Finally, immunohistochemical analyses showed 8S-LOX protein expression was strictly confined to the differentiated compartment of mouse skin and throughout tumorigenesis. Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis.