Showing papers on "7,12-Dimethylbenz[a]anthracene published in 2006"

Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2.

Abstract: Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.

Anticancer and antimutagenic properties of Acacia nilotica (Linn.) on 7,12-dimethylbenz(a)anthracene-induced skin papillomagenesis in Swiss albino mice.

Abstract: We report the chemopreventive activity of Acacia nilotica (Linn.) gum, flower and leaf aqueous extracts, on 7,12-dimethylbenz(a)anthracene (DMBA) induced skin papillomagenesis in male Swiss albino mice. Animals were divided into following groups: Group I (Controls) given DMBA and croton oil, with no extract ; Group II (treatment) animals treated with Acacia nilotica gum (Group II-a) (800 mg/kg body weight), flowers (Group II-b) (800 mg/kg body weight), or leaves (Group II-c) (800 mg/kg body weight) during the peri- and post initiation periods of DMBA and croton oil application. A significant reduction in the values of tumor burden, tumor incidence and cumulative number of papillomas was observed in mice treated by oral gavage with the Acacia nilotica gum, flower and leaf extracts as compared with the control group. The latency period in treatment Group-II (b) and Group-II (c) was significantly increased as compared with the control group. A significant reduction in the frequency of micronuclei was also observed in mice treated by oral gavage with the aqueous extracts, along with significant decrease in total chromosomal aberrations in the form of chromatid breaks, chromosome breaks, centric rings, dicentrics, acentric fragments and exchange. Treatment with Acacia nilotica flower (Group II-B) and leaf (Group II-C) aqueous extracts by oral gavage for 15 days resulted in a highly significant decrease in the lipid peroxidation (LPO) level in the liver, but this was less evident with the gum (Group II-A) . Conversely, reduced glutathione (GSH) content was observed to be significantly elevated as compared with the control group with leaves (Group II-C) and flowers (Group II-B). The chemopreventive and antimutagenic activity of the leaf extract of Acacia nilotica was most significant followed by the flower extract and then by gum.

Anticarcinogenic and antilipidperoxidative effects of Tephrosia purpurea (Linn.) Pers. in 7, 12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinoma

Abstract: Objectives: To investigate the chemopreventive potential and antilipidperoxidative effects of ethanolic root extract of Tephrosia purpurea (Linn.) Pers. (TpEt) on 7,12-dimethylbenz(a)anthracene (DMBA)- induced hamster buccal pouch carcinoma. Materials and Methods: Oral squamous cell carcinoma was developed in the buccal pouch of Syrian golden hamsters, by painting with 0.5% DMBA in liquid paraffin, thrice a week, for 14 weeks. The tumor incidence, volume and burden were determined. Oral administration of TpEt at a dose of 300 mg/kg, b.w., to DMBA (on alternate days for 14 weeks)- painted animals significantly prevented the incidence, volume and burden of the tumor. Results: TpEt showed potent antilipidperoxidative effect, as well as enhanced the antioxidant status in DMBA- painted animals. Conclusion: TpEt has potent chemopreventive efficacy and significant antilipidperoxidative effect, in DMBA-induced oral carcinogenesis. Further studies are needed to isolate and characterize the bioactive principle.

7,12-Dimethylbenz(a)Anthracene Treatment of a c-rel Mouse Mammary Tumor Cell Line Induces Epithelial to Mesenchymal Transition via Activation of Nuclear Factor-κB

Abstract: The aberrant expression of the nuclear factor-κB (NF-κB) c-Rel subunit that occurs in many human breast cancers can play a causal role in tumorigenesis as judged by findings with a mouse mammary tumor virus (MMTV)-c- rel transgenic mouse model, in which 31.6% of mice developed one or more mammary tumors after a long latency. Interestingly, none of the cell lines established from the mammary tumors grew in soft agar. To begin to test the hypothesis that a prototypic carcinogen insult can promote a more invasive, mesenchymal phenotype, a cell line established from a MMTV-c- rel mammary tumor rel-3983 was treated in culture with the polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA; rel-3983D cells) or DMSO vehicle (rel-3983V cells). Rel-3983D cells displayed an increased rate of proliferation, displayed growth to a higher cell density, and acquired the ability to grow in soft agar and in Matrigel compared with the parental rel-3983 or vehicle-treated rel-3983V cells. Consistent with a more mesenchymal phenotype, rel-3983D cells showed loss of E-cadherin expression as judged by immunofluorescence microscopy. Compared with control cells, rel-3983D displayed increased NF-κB binding and higher levels of the NF-κB transactivating subunits c-Rel, RelA, and RelB, which seemed functional as judged by induction of c-Myc and vimentin, products of two NF-κB target genes. Ectopic expression of a super repressor mutant of IκB-α reduced rel-3983D cell growth and invasive morphology in Matrigel, confirming the role of NF-κB in epithelial to mesenchymal transition (EMT). Thus, DMBA treatment of c-Rel–transformed mammary tumor cells in culture is shown here for the first time to result in EMT via activation of NF-κB. The aberrant c-Rel expression present in most human breast cancers suggests that this mechanism may play an important role in carcinogenesis. (Cancer Res 2006; 66(5): 2570-5)

Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors.

Abstract: Previous studies have shown that aberrant arachidonic acid (AA) metabolism, especially cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-Lox) pathways, are activated during oral carcinogenesis, and can be targeted for cancer prevention. This study was designed to investigate the importance of 5-Lox/leukotriene A4 hydrolase (LTA4H) pathway of AA metabolism in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis. In a short-term study, topical application of DMBA for 3 weeks induced severe inflammation and aberrant AA metabolism. Subsequent topical treatment with zileuton, celecoxib, or their combination for 1 week significantly suppressed aberrant AA metabolism and cell proliferation in the oral epithelium. Interestingly, zileuton was effective in inhibiting biosynthesis of multiple AA metabolites, including leukotriene B4 (LTB4), 5-, 12-, 15-hydroxyeicosatetraenoic acid and prostaglandin E2 (PGE2), while celecoxib only suppressed PGE2 biosynthesis significantly at a high dose. In a long-term carcinogenesis study topical application of LTB4 or PGE2 enhanced oral carcinogenesis by increasing the incidence and volume of visible tumors, and the incidence of squamous cell carcinoma (SCC). To further examine the role of LTB4 in oral carcinogenesis, two LTA4H inhibitors, bestatin and SA6541, were evaluated in a long-term chemoprevention experiment. Both agents significantly inhibited SCC, and such an inhibition correlated with reduced levels of LTB4 in hamster cheek pouch. In summary, our studies have demonstrated that 5-Lox/LTA4H pathway is one of the major AA-metabolizing pathways involved in DMBA-induced oral carcinogenesis in hamsters, and may be targeted for chemoprevention.

Evaluation of anticarcinogenic effects of Clerodendron inerme on 7,12-dimethylbenz(a) anthracene-induced hamster buccal pouch carcinogenesis

Abstract: INTRODUCTION Oral cancer is the fifth most frequent cancer worldwide and India has recorded the highest incidence (40-50 percent) of oral malignancy. Clerodendron inerme is used by Indian traditional practitioners for the treatment of various ailments, including cancer. Our aim was to investigate the chemopreventive potential of the aqueous leaf extract of Clerodendron inerme (CiAet) in 7,12-dimethylbenz(a) anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. METHODS We developed oral squamous cell carcinoma in the buccal pouch of male Syrian golden hamsters by painting them with 0.5% DMBA in liquid paraffin thrice a week for 14 weeks. The tumour incidence, tumour volume and tumour burden that were formed in the hamster buccal pouches were determined. RESULTS Oral administration of CiAet at a dose of 500 mg/kg body weight to DMBA-painted animals on days alternate to DMBA painting for 14 weeks significantly prevented the tumour incidence, tumour volume and tumour burden. CiAet also exerts potent antilipidperoxidative effect and improved the antioxidant defence system in DMBA-painted animals. The chemopreventive efficacy of CiAet was evident by inhibition of tumour formation (80%) in DMBA-painted animals. CONCLUSION The chemopreventive potential of CiAet is probably due to its antilipidperoxidative effect or the presence of some potent bioactive chemopreventive principles in the leaves of Clerodendron inerme.

Naturally occurring coumarins inhibit 7,12-dimethylbenz[a]anthracene DNA adduct formation in mouse mammary gland.

Abstract: Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g. coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g. imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg body wt, by gavage) prior to either a single dose of DMBA (50 microg) or multiple doses of DMBA (20 microg daily for 3 and 6 weeks). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin and isopimpinellin inhibited DMBA-DNA adduct formation by 50, 41, 79 and 88%, respectively. Coumarin, limettin and imperatorin blocked DMBA-DNA adduct formation by 36, 60, and 66% at 3 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0, 43 and 24% in the limettin groups; by 26, 26 and 69% in the isopimpinellin groups; and by 80, 96 and 97% in the 7,8- benzoflavone groups at 35, 70 and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared with simple coumarins, and that the predominant effect may be P4501 inhibition.

Effect of Rosmarinus officinalis in modulating 7,12-dimethylbenz(a)anthracene induced skin tumorigenesis in mice.

Abstract: The chemopreventive potential of rosemary (Rosmarinus officinalis) on 7,12-dimethlybenz(a)anthracene (DMBA) initiated and croton oil promoted mouse skin tumorigenesis was assessed. The modulatory effects of R. officinalis was monitored on the basis of the average latency period, tumor incidence, tumor burden, tumor yield, tumor weight and diameter as well as lipid peroxidation and glutathione level. The results indicate that R. officinalis leaves extract could prolong the latency period of tumor occurrence, decrease the tumor incidence, tumor burden and tumor yield. The average weight and diameter of tumors recorded were comparatively lower in the rosemary extract treated mouse groups. The level of lipid peroxidation was significantly reduced in blood serum and liver. Furthermore, depleted levels of glutathione were restored in RE-administered animal groups. Thus, at a dose rate of 500 mg/kg body wt/mouse, the oral administration of rosemary extract was found to be significantly protective against two-stage skin tumorigenesis.

Inhibitory effects of Azadirachta indica on DMBA-induced skin carcinogenesis in Balb/c mice

Abstract: Male Balb/c mice were divided into four groups on the basis of their respective treatments wherein mice of Group I served as controls. For induction of skin tumors, mice of Group II and IV were injected sub-cutaneously with 7,12-dimethylbenz(a)anthracene (DMBA). Mice of Group III and IV were administered aqueous Azadirachta indica leaf extract (AAILE) thrice a week throughout the experiment. After 14 weeks of the first DMBA injection, Group II and IV mice developed tumors. In the tumor-bearing mice that received AAILE (Group IV), a significant reduction in mean tumor burden and tumor volume was observed. The tumors were confirmed to be papillomas and interestingly, the extent of hyper-chromatia was observed to be much more in skin tumors of Group II mice vis a vis the mice receiving AAILE. An increase in the extent of lipid peroxidation was observed in tumorous tissue of Group IV when compared to that of Group II mice. Glutathione (GSH) content and the activities of GSH-based antioxidant enzymes viz. glutathione peroxidase (GPx) and glutathione reductase (GR) increased significantly in the skin tissues of all the groups of mice when compared to control counterparts. Catalase activity was found to decrease significantly in the skin of mice, which received AAILE treatment only (Group III). Activity of super-oxide dismutase (SOD) decreased significantly in all the tumorous tissues (Group II and IV mice). In light of the above observations, the role of AAILE in inhibition of DMBA-induced skin carcinogenesis is discussed in the present study.

Chemopreventive potential of Tribulus terrestris against 7,12- dimethylbenz (a) anthracene induced skin papillomagenesis in mice.

Abstract: In the present investigation, the chemopreventive potential of aqueous extracts of the root and fruit of Tribulus terrestris (an Ayurvedic medicinal plant) on 7, 12 - dimethylbenz (a) anthracene (DMBA) induced papillomagenesis in male Swiss albino mice was studied. A significant reduction in tumor incidence, tumor burden and cumulative number of papillomas was observed, along with a significant increase in average latent period in mice treated orally with Tribulus terrestris suspension continuously at pre, peri and post-initiation stages of papillomagenesis as compared to the control group treated with DMBA and croton oil alone. Treatment with Tribulus terrestris suspension by oral gavage for 7 days resulted in a significant increase in the reduced glutathione content in the liver (P< 0.001 for both root and fruit extracts). Conversely, lipid peroxidation levels were significantly decreased (P< 0.001).

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Abstract: Purpose: Synthetic progestins are widely used therapeutically; however, there is controversy regarding their proliferative effects. We used a rat 7,12-dimethylbenz[ a ]anthracene (DMBA)–induced mammary tumor model to test the hypothesis that progestins increase angiogenesis and as a result decrease the latency period and increase the multiplicity of mammary tumors. Experimental Design: Medroxyprogesterone acetate (MPA) pellets were implanted 2, 4, or 6 weeks after DMBA exposure; RU-486 was given 3 days before MPA. Experiments were concluded 70 days after DMBA administration. Results: MPA exposure 4 or 6 weeks after DMBA reduced the latency period for appearance of tumors in a dose-dependent manner and increased tumor incidence. Administration of MPA 2 weeks after DMBA administration reduced tumor incidence and was protective. Progesterone did not reduce the latency period but significantly increased tumor incidence. RU-486 delayed the latency period and decreased tumor incidence in animals exposed to MPA at 4 weeks after DMBA treatment, indicating that the progesterone receptor may be partially responsible for transmission of proliferative signals. RU-486 also delayed the latency period but failed to reduce overall tumor incidence when animals were exposed to MPA at 6 weeks after DMBA treatment, indicating that other factors may also control MPA-induced acceleration. Whereas MPA-accelerated tumors were both intraductal and tubular, progesterone-accelerated and/or DMBA-induced tumors were tubular. Progestin treatment increased vascular endothelial growth factor expression within tumors in a ligand- and cell type–dependent manner and increased angiogenesis in correlation with vascular endothelial growth factor expression. No mammary tumors or progesterone receptor were detected in DMBA-treated ovariectomized rats regardless of progestin administration. Conclusions: We propose that progestins can accelerate the development of mammary tumors and that antiangiogenic agents and/or the use of antiprogestins that can reduce tumor incidence might be a viable therapeutic option for treatment of progestin-accelerated tumors. The model described here is a potentially useful preclinical model for rapidly screening such compounds.

Effect of biochanin A on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells

Abstract: Phytoestrogen biochanin A is an isoflavone derivative isolated from red cloverTrifolium pratense with anticarcinogenic properties. This study examined the action of biochanin A with the carcinogen activation pathway that is mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 breast carcinoma cells. Treating the cells with biochanin A alone caused the accumulation of CYP1A1 mRNA and an increase in CYP1A1-specific 7-ethoxyresorufinO-deethylase (EROD) activity in a dose dependent manner. A concomitant treatment with 7, 12-dimethylbenz[a]anthracene (DMBA) and biochanin A markedly reduced the DMBA-inducible EROD activity and CYP1A1 mRNA level. In addition, the biochanin A treatment alone activated the DNA-binding capacity of the AhR for the dioxin-response element (DRE) of CYP1A1, as measured by the electrophoretic-mobility shift assay (EMSA). EMSA revealed that biochanin A reduced the level of the DMBA-inducible AhR-DRE binding complex. Furthermore, biochanin A competed with the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), for binding to the AhR in an isolated rat cytosol. The biochanin A competitively inhibited the metabolic activation of DMBA, as measured by the formation of the DMBA-DNA adducts. These results suggest that biochanin A may thus be a natural ligand to bind on AhR. Therefore, biochanin A may be due to act an antagonist/agonist of the AhR pathway.

Gene expression profiling in the mammary gland of rats treated with 7,12-dimethylbenz[a]anthracene.

Abstract: Identification of molecular markers of early-stage breast cancer development is important for the diagnosis and prevention of the disease. In the present study, we used microarray analysis to examine the differential expression of genes in the rat mammary gland soon after treatment with a known chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), and prior to tumor development. Six weeks after DMBA, differential expression of multiple genes involved in cell growth, differentiation and microtubule dynamics were observed. Gene expression changes were further validated by a combination of techniques, including real-time PCR, RT-PCR, Western blotting and immunohistochemistry. An inhibition of differentiation in this early stage was suggested by the lower expression of β-casein and transferrin and higher expression of hsp27 in glands from DMBA-treated rats. Possible cell cycle deregulation was indicated by an increased expression of cyclin D1 and hsp86, a heat shock protein associated with cyclin D1. Prior to tumor development, DMBA increased cellular proliferation as detected by Ki-67 and stathmin immunostaining in histologically normal mammary gland. Genes regulating microtubule function, including stathmin, Ran, α-tubulin and hsp27, were all overexpressed in the mammary gland of DMBA-treated rats, raising the possibility that disruption of microtubule dynamics and abnormal mitosis may be critical events preceding breast cancer development. Several of the altered proteins, including hsp27, hsp86 and stathmin, may ultimately serve as markers of early breast cancer development. Published 2005 Wiley-Liss, Inc.

Black tea polyphenols protect against 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

Abstract: Dietary chemoprevention has emerged as a cost-effective approach for cancer control. We evaluated the chemopreventive effects of black tea polyphenols (Polyphenon-B) administration during the preinitiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. The expression of proliferating cell nuclear antigen (PCNA) in the buccal pouch and the concentration of lipid peroxides, protein carbonyl, and the antioxidant status in the buccal pouch, liver and erythrocytes were used as biomarkers of chemoprevention. All the hamsters painted with DMBA alone for 14 weeks developed buccal pouch carcinomas associated with increased expression of PCNA, diminished lipid and protein oxidation, and enhanced antioxidant status. In the liver and erythrocytes of tumor-bearing animals, enhanced oxidation of lipids and proteins was accompanied by compromised antioxidant defenses. Dietary administration of Polyphenon-B effectively suppressed DMBA-induced HBP carcinogenesis as revealed by decreased incidence of tumours and PCNA expression. In addition, Polyphenon-B modulated lipid and protein oxidation and enhanced the antioxidant status in the pouch, liver, and erythrocytes. We suggest that Polyphenon-B exerts its chemopreventive effects by inhibiting cell proliferation in the target tissue and modulating the oxidant-antioxidant status in the target as well as in host tissues.

Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue® transgenic rats

Abstract: The major constituents of isoflavones, daidzein (DZ) and genistein (GE) are known to interact with the alpha and beta estrogen receptors (ERalpha/beta) in several tissues including mammary. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E2) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue (BB) transgenic rats. The rats were fed control diet containing the isoflavones and E2 and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND 50. Animals were sacrificed at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E2 supplementation alone resulted in modest increases in the lacI MF that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lacI MFs in the mammary of both OVX and ovary intact (INT) rats and Hprt MFs in spleen lymphocytes (P

Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine.

Abstract: Several lines of evidence suggest that stem cells are major targets for carcinogens. A normal human breast epithelial cell type was previously shown to possess stem cell characteristics. Further cell lines were derived following sequential transfection with SV40 large T-antigen (immortal, non-tumorigenic M13SV1 cells), exposure to X-rays (weakly tumorigenic M13SV1R2 cells), and ectopic expression of c-erbB2/neu (highly tumorigenic M13SV1R2N1 cells). We evaluated some characteristics of these cells and their susceptibility to the breast carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Compared to M13SV1 cells, the two untreated tumorigenic cell lines displayed higher levels of connexin 43 expression and NF-kappaB nuclear translocation, and a higher frequency of fhit loss. The baseline nuclear translocation of AP-1 and pCREB was particularly evident in M13SV1R2N1 cells and was further enhanced by DMBA treatment, indicating an interaction between c-erbB2/neu and DMBA-induced signalling. Treatment with DMBA did neither affect the baseline fhit loss nor p53 mutation, whereas it increased NF-kappaB nuclear translocation, the proportion of apoptotic cells, and the levels of connexin 43, common 4977-bp mitochondrial DNA deletion, and bulky adducts to nuclear DNA. DMBA-treated M13SV1 cells underwent significant oxidative DNA damage and exhibited the highest DNA adduct levels, while they had the lowest apoptotic rate. Co-treatment of cells with N-acetylcysteine (NAC) attenuated DMBA-induced toxicity and DNA alterations, particularly in M13SV1 cells. Thus, the immortal cell line derived from the normal human adult breast stem cell without further tumorigenic progression is the most susceptible both to DMBA-related alterations and to the protective effects of NAC.

The aspirin metabolite, salicylate, inhibits 7,12-dimethylbenz[a]anthracene-DNA adduct formation in breast cancer cells.

Abstract: There is evidence that aspirin and other non-steroidal anti-inflammatory drugs may be protective agents against cancer in the gastrointestinal tract. These effects are particularly well documented for the colon and rectum. Some epidemiological and experimental studies have suggested that aspirin could also be a chemopreventive agent against breast cancer. We investigated the effects of the aspirin metabolite, salicylate (SA), on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation as well as on the expression of the enzymes involved in the carcinogen bioactivation pathway, in particular cytochrome P450 1A (CYP1A) and cyclooxygenases (COX-1 and COX-2). The effects of the test drug were examined in both the human mammary carcinoma cell line, MCF-7, and mammary cells derived from DMBA-induced rat mammary tumours (RMTCs). In this study, we also reported the effects of SA on cell growth and viability in breast cancer cells (BCCs). The results demonstrated that DMBA-DNA adduct formation in both cancer cell lines was inhibited by SA at concentrations of > or = 2.5 mM. CYP1A was undetectable in RMTCs while CYP1A induction by beta-naphthoflavone in MCF-7 cells was significantly inhibited by SA in a concentration-dependent manner. Aspirin did not affect COX-1 expression in either of the BCCs. COX-2 was not detected in MCF-7 cells, but its expression in RMTCs was inhibited by SA treatment, which also significantly reduced BCC growth, but failed to cause cell death by necrosis or apoptosis. These data suggest that inhibition of DMBA-DNA adduct formation may contribute to aspirin breast cancer chemopreventive action and indicate that this drug can act in the first stage of carcinogenesis.

Effects of 7,12-dimethylbenz(a)anthracene on growth and haematological parameters in Korean rockfish, Sebastes schlegeli (Hilgendorf)

Abstract: The objectives of the present experiment were to determine the effects on growth factors and some haematological parameters in Korean rockfish, Sebastes schlegeil, after dietary 7,12-dimethylbenz(a)anthracene (DMBA) exposure at 0.6, 1.2, 2.4 and 4.8 mg kg[superscript [-]1] diet for 8 weeks. The specific growth rate of the fish exposed to DMBA ([>/=]1.2 mg kg[superscript [-]1]) showed significantly lower performance than the control. Following 8 weeks of exposure, the DMBA-exposed groups (2.4 and 4.8 mg kg[superscript [-]1]) had a significantly higher mean hepatosomatic index. Condition factor of the fish exposed to DMBA did not show any statistically significant deviation from the control (P>0.05), although the mean values were somewhat lower than those of the control group. Observations on haematological parameters indicated DMBA treatment induced a severe anaemia. Total protein, albumin and total cholesterol concentrations decreased following exposure to DMBA at 2.4 and 4.8 mg kg[superscript [-]1]. In contrast, serum bilirubin and blood urea nitrogen in fish exposed to DMBA increased. Significant decreases in serum electrolytes, chloride, phosphorus, magnesium and calcium, and osmolality were observed in all DMBA-treatment groups. All DMBA-treatment groups showed a significantly higher activity of lactate dehydrogenase and alkaline phosphatase. Serum transaminase activity after the highest level of 4.8 mg kg[superscript [-]1] DMBA was significantly increased. The key finding from this study is that rockfish exposed to dietary DMBA at concentrations of 1.2 and 2.4 mg kg[superscript [-]1] diet are likely to experience adverse impacts in growth and haematological property respectively.

Enhancement of erythrocyte antioxidants by green and black tea polyphenols during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

Abstract: We evaluated the comparative chemopreventive efficacy of green tea polyphenols (polyphenon-E) and black tea polyphenols (polyphenon-B) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster bucca...