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Molecular Carcinogenesis Aug 2019Substantial evidence suggests that 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in mice mimics human breast cancer (BC) in many respects. Therefore,...
Substantial evidence suggests that 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis in mice mimics human breast cancer (BC) in many respects. Therefore, it has been used extensively to evaluate preventive and therapeutic agents for human BC. Mammary carcinogenesis induced by DMBA administration in female SENsitive to CARcinogen (SENCAR) mice was characterized by histopathological analysis of the mammary glands and alterations to the phosphatidylinositol 3-kinase/protein kinase B/cyclin-dependent kinase 1 (PI3K/Akt/CDK1) pathway. We recently reported that 2'-hydroxyflavanone (2HF) is a promising diet-derived chemotherapeutic agent that suppresses BC growth in vitro and in vivo by targeting a 76 kDa ral-interacting protein (RLIP). The objective of the current study was to investigate the synergistic anticarcinogenic effects of RLIP inhibition/depletion and 2HF in an in vivo model of DMBA-induced mammary carcinogenesis in SENCAR mice. Mice were given 2HF (50 mg/kg, bw, orally on alternate days), RLIP antibody (Rab; 5 mg/kg, bw, ip weekly), RLIP antisense (RAS; 5 mg/kg, b.w., ip weekly), or a combination of 2HF + Rab + RAS. Animals were monitored daily, and 7 days after the first appearance of moribund behavior, tissues were harvested for morphological and immunohistological analysis. Western blot analyses were performed to determine the expression of anti- and proapoptotic proteins in the mammary glands. Our results reveal that 2HF, RAS, and Rab significantly prevented the carcinogenic effects of DMBA administration in the mammary glands and other organs. Further, mice treated with a combination of 2HF + RAS + Rab exhibited no carcinogenic effect of DMBA as compared to either or the single agent-treated mice. This study demonstrates for the first time the anticarcinogenic effects of 2HF and RLIP inhibition/depletion in vivo in a novel DMBA-induced model of BC in SENCAR mice and provides the rationale for further clinical investigation.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; CDC2 Protein Kinase; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Flavanones; GTPase-Activating Proteins; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred SENCAR; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 31006917
DOI: 10.1002/mc.23026 -
DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A.The Journal of Cell Biology Aug 2021Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of...
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; CCAAT-Enhancer-Binding Protein-beta; Cell Cycle Checkpoints; Cell Proliferation; Cellular Senescence; DNA Methylation; Epigenesis, Genetic; Female; Fibroblasts; HEK293 Cells; Histone-Lysine N-Methyltransferase; Histones; Humans; Interleukin-1alpha; Membrane Proteins; Mice; Microscopy, Fluorescence; Papilloma; Phenotype; Secretory Pathway; Skin Neoplasms; Tetradecanoylphorbol Acetate
PubMed: 34037658
DOI: 10.1083/jcb.202008101 -
Cancer Letters Apr 2021Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent...
Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Aromatase; Breast Neoplasms; Cell Line, Tumor; Chemokine CCL2; Cyclooxygenase 2; Diet, High-Fat; Dinoprostone; Disease Models, Animal; Etoricoxib; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; MCF-7 Cells; Medroxyprogesterone Acetate; Mice; Sugars; Up-Regulation
PubMed: 33429006
DOI: 10.1016/j.canlet.2021.01.003 -
Asian Pacific Journal of Cancer... Mar 2022Breast cancer prevention still needs to be improved. Calorie restriction is thought to prevent breast cancer through the induction of autophagy. Maranta arundinacea L....
BACKGROUND
Breast cancer prevention still needs to be improved. Calorie restriction is thought to prevent breast cancer through the induction of autophagy. Maranta arundinacea L. (MA) has the potential for calorie restriction because it contains high fiber. This research aimed to observe the effect of dietary MA against dimethylbenz(a)anthracene (DMBA)-induced mammary cancer in Sprague Dawley rats related to autophagy.
METHODS
Twenty-five Sprague Dawley rats were randomly divided into five groups: 1) control group without DMBA-induced with a standard diet, 2) 20 mg/kg BW of DMBA two times a week for five weeks with a standard diet, 3) DMBA and diet modification with 30% of MA, 4) DMBA and diet modification with 45% of MA, and 5) DMBA and diet modification with 60% of MA. Examination of the nodule was conducted once every week for 22 weeks. Breast tissue/tumor examination underwent histology examination with hematoxylin-eosin. Examinations of immunohistochemical staining against Beclin1, LC3B, and SQSTM1 were conducted to reveal autophagy. The difference of autophagy protein expression was analyzed using One way ANOVA with 95% confidence level and significance set as p<0.05.
RESULTS
Cancer was detected in four rats of DMBA standard diet, two rats of 30% MA, one rat of 45% MA. No cancer was detected in the rats of control and rats with 60% of MA group. The Beclin1 expressions showed that the 60% of MA group had the highest score (2.5±0.52) followed by the 45% of MA group (1.87±0.49), control group (1.77±0.11), 30% of MA group (1.28±0.75), and DMBA with standard diet had the lowest score (1.28±0.91). The difference of Beclin1 expressions was statistically significant (p-value=0.03). However, the difference of the LC3B expressions (p-value=0.11) and SQSTM1 expressions (p-value=0.225) were not statistically significant.
CONCLUSION
Dietary modifications with MA potentially prevent breast cancer and induce initiation of autophagy.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Autophagy; Breast Neoplasms; Diet; Female; Humans; Mammary Neoplasms, Experimental; Marantaceae; Rats; Rats, Sprague-Dawley
PubMed: 35345372
DOI: 10.31557/APJCP.2022.23.3.985 -
The Journal of Investigative Dermatology Oct 2020We previously revealed the crucial roles of a chemokine, CX3CL1, and its receptor, CX3CR1, in skin wound healing. Although repeated wounds frequently develop into skin...
We previously revealed the crucial roles of a chemokine, CX3CL1, and its receptor, CX3CR1, in skin wound healing. Although repeated wounds frequently develop into skin cancer, the roles of CX3CL1 in skin carcinogenesis remain elusive. Here, we proved that CX3CL1 protein expression and CX3CR1 macrophages were observed in human skin cancer tissues. Similarly, we observed the enhancement of CX3CL1 expression and the abundant accumulation of CX3CR1 tumor-associated macrophages with M2-like phenotypes in the skin carcinogenesis process induced by the combined treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. In this mouse skin carcinogenesis process, CX3CR1 tumor-associated macrophages exhibited M2-like phenotypes with the expression of Wnt3a and angiogenic molecules including VEGF and matrix metalloproteinase 9. Compared with wild-type mice, CX3CR1-deficient mice showed fewer numbers of skin tumors with a lower incidence. Concomitantly, M2-macrophage numbers and neovascularization were reduced with the depressed expression of angiogenic factors and Wnt3a. Thus, the CX3CL1-CX3CR1 axis can crucially contribute to skin carcinogenesis by regulating the accumulation and functions of tumor-associated macrophages. Thus, this axis can be a good target for preventing and/or treating skin cancers.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; CX3C Chemokine Receptor 1; Cell Movement; Chemokine CX3CL1; Humans; Male; Mice; Mice, Inbred C57BL; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tumor-Associated Macrophages; Wnt3A Protein
PubMed: 32179066
DOI: 10.1016/j.jid.2020.02.023 -
Acta Cirurgica Brasileira 2019To examine the effects of Arrabidaa chica (Bignoniacea) extract, a native plant of the Amazon known as crajiru, on a 7,12-dimethyl-1,2-benzanthracene (DMBA)-induced...
PURPOSE
To examine the effects of Arrabidaa chica (Bignoniacea) extract, a native plant of the Amazon known as crajiru, on a 7,12-dimethyl-1,2-benzanthracene (DMBA)-induced breast cancer model in Wistar rats.
METHODS
We compared the response of breast cancer to the oral administration of A. chica extract (ACE) for 16 weeks, associated or not with vincristine. Groups: normal control; DMBA (50mg/kg v.o,) without treatment; DMBA+ACE (300 mg/kg); DMBA+vincristine. 500μg/kg injected i.p; DMBA+ACE+Vincristine 250μg/kg i.p. Imaging by microPET and fluorescence, biochemistry, oxidative stress, hematology and histopathology were used to validate the treatments.
RESULTS
All animals survived. A gradual weight gain in all groups was observed, with no significant difference (p>0.05). The oral administration of ACE and ACE+vincristine 50% significantly reduced breast tumors incidence examined with PET-18FDG and fluorescence (p<0.001). Significant reduction of serum transaminases, oxidative stress and hematological toxicity were observed in these groups. Antioxidant enzyme levels in breast tissue were significantly higher compared to the DMBA and DMBA+vincristine groups.
CONCLUSION
These results demonstrate for the first time that ACE positively influences the treatment of DMBA-induced breast cancer in animal model, inducing a reduction in oxidative stress and chemotherapy toxicity, meaning that ACE may have clinical implication in further studies.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Bignoniaceae; Breast Neoplasms; Carcinogens; Carcinoma; Catalase; Female; Fluorodeoxyglucose F18; Glutathione Peroxidase; Neoplasms, Experimental; Optical Imaging; Oxidative Stress; Plant Extracts; Positron-Emission Tomography; Radiopharmaceuticals; Rats, Wistar; Reproducibility of Results; Superoxide Dismutase; Time Factors; Treatment Outcome; Vincristine
PubMed: 31826147
DOI: 10.1590/s0102-865020190100000001 -
Archives of Dermatological Research Oct 2019Wnt pathway plays an important role in controlling metabolism in cancer cells. It acts as positive modulator for both cell inflammation, through activation of NFκB, and...
Wnt pathway plays an important role in controlling metabolism in cancer cells. It acts as positive modulator for both cell inflammation, through activation of NFκB, and fibrosis, through activation of TGF-β. Therefore, the aim of this study is to investigate the therapeutic effects of blocking Wnt pathway by IWP12 on skin cancer by studying its effects on skin cancer-induced inflammation and fibrosis in a mice model of skin cancer. Skin cancer was induced by application of 7,12-dimethylbenz[a]anthracene (DMBA) and croton oil on the dorsal skin of mice. Dorsal skin was removed for estimation of gene and protein expression of Wnt, β-catenin, SMAD, TGF-β, NFκB, TNF-α, IL-4 and IL-10. Part of the skin is stained with hematoxylin/eosin for assessment of cell structure. Treatment of mice with IWP12 completely blocked Wnt in skin cancer mice without affecting the control mice. Skin of tumorigenic mice showed marked skin hyperkeratosis, parakeratosis, acanthosis and dysplasia. Treatment with IWP12 markedly attenuated epidermal atypia and hyperplasia. In addition, IWP12 reduced expression of β-catenin, SMAD, TGF-β, NFκB and TNF-α associated with increase in the expression of IL-4 and IL-10. In conclusion, blocking Wnt production ameliorated skin cancer via blocking pro-inflammatory cytokines and enhancing the anti-inflammatory cytokines. Moreover, blocking Wnt attenuated skin cancer-induced activation of fibrosis pathway.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinogenesis; Croton Oil; Cytokines; Drug Screening Assays, Antitumor; Epidermis; Fibrosis; Gene Expression Regulation, Neoplastic; Humans; Mice; NF-kappa B; Neoplasms, Experimental; Skin Neoplasms; Wnt Proteins; Wnt Signaling Pathway
PubMed: 31165240
DOI: 10.1007/s00403-019-01939-4 -
Toxics Aug 2022The safety evaluation of food contact materials requires excluding mutagenicity and genotoxicity in migrates. Testing the migrates using in vitro bioassays has been...
The safety evaluation of food contact materials requires excluding mutagenicity and genotoxicity in migrates. Testing the migrates using in vitro bioassays has been proposed to address this challenge. To be fit for that purpose, bioassays must be capable of detecting very low, safety relevant concentrations of DNA-damaging substances. There is currently no bioassay compatible with such qualifications. High-performance thin-layer chromatography (HPTLC), coupled with the planar SOS Umu-C (p-Umu-C) bioassay, was suggested as a promising rapid test (~6 h) to detect the presence of low levels of mutagens/genotoxins in complex mixtures. The current study aimed at incorporating metabolic activation in this assay and testing it with a set of standard mutagens (4-nitroquinoline--oxide, aflatoxin B1, mitomycin C, benzo(a)pyrene, -ethyl nitrourea, 2-nitrofluorene, 7,12-dimethylbenzanthracene, 2-aminoanthracene and methyl methanesulfonate). An effective bioactivation protocol was developed. All tested mutagens could be detected at low concentrations (0.016 to 230 ng/band, according to substances). The calculated limits of biological detection were found to be up to 1400-fold lower than those obtained with the Ames assay. These limits are lower than the values calculated to ensure a negligeable carcinogenic risk of 10. They are all compatible with the threshold of toxicological concern for chemicals with alerts for mutagenicity (150 ng/person). They cannot be achieved by any other currently available test procedures. The p-Umu-C bioassay may become instrumental in the genotoxicity testing of complex mixtures such as food packaging, foods, and environmental samples.
PubMed: 36136466
DOI: 10.3390/toxics10090501 -
Journal of Biochemical and Molecular... Jul 2021The aim of the present study is to explore the preventive efficacy of betulin (BE) in 7,12-dimethylbenz(a)anthracene (DMBA)-administered mammary cancer by modulating...
The aim of the present study is to explore the preventive efficacy of betulin (BE) in 7,12-dimethylbenz(a)anthracene (DMBA)-administered mammary cancer by modulating Ahr/Nrf2 signaling in experimental models. The mammary cancer was stimulated by the addition of DMBA (25 mg/kg/b.Wt) mixed in 1 ml of vehicle solution (sunflower oil and saline 1:1) through subcutaneous injection. The DMBA-exposed mammary tumor models showed low bodyweight, elevated quantities of lipid peroxidation molecules (TBARS and LOOH), and low enzymatic (GPx, SOD, and CAT), and nonenzymatic (GSH, vitamin C, and vitamin E) antioxidant activities in plasma and mammary tissues. Moreover, histopathological studies confirmed that invasive ductal carcinoma was observed in DMBA-induced mammary tissue of the experimental model. Dietary oral supplementation of BE prevents the loss of bodyweight, overproduces lipid peroxidation, and restores the antioxidant activities in DMBA-exposed experimental animals. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial antioxidant protein that involves preventing numerous cancers. Therefore, Nrf2-associated signaling concern is a significant target for preventing mammary cancer. This study observed an increased expression of MAPKs, Keap1, ARNT, AhR, and CYP1A1, whereas decreased expression of HO-1 and Nrf2 in DMBA-induced cancer-bearing experimental animals. The oral supplementation of BE effectively modulates the expression of MAPKs, AhR/Nrf2-associated protein expressions in DMBA-exposed experimental animals. This current study concluded that BE is a strong antioxidant, which triggers the MAPKs-mediated oxidative stress and inhibits proliferative markers by restoring the activity of Nrf2 signaling.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Female; MAP Kinase Signaling System; Mammary Neoplasms, Animal; NF-E2-Related Factor 2; Neoplasm Proteins; Rats; Receptors, Aryl Hydrocarbon; Triterpenes
PubMed: 33759307
DOI: 10.1002/jbt.22779 -
International Journal For Vitamin and... Sep 2021The present study aimed to examine the chemoprotective effect of Hydroethanolic leaves extract (HEMKLE) on murine skin carcinogenesis model. For the study, male LACA...
The present study aimed to examine the chemoprotective effect of Hydroethanolic leaves extract (HEMKLE) on murine skin carcinogenesis model. For the study, male LACA mice divided into four groups (n = 15 per group). Group I (Control), Group II (DMBA/TPA), Group III (HEMKLE), and Group IV (HEMKLE + DMBA/TPA). Skin tumors were induced in Group II (DMBA/TPA) and Group IV (HEMKLE + DMBA/TPA) by topical application of 7, 12 dimethylbenz[a]anthracene (DMBA) [500 nmol/100 μL of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7 nmol/100 μL of acetone, twice a week for eighteen weeks] and HEMKLE (200 mg/kg b. w.) was administered orally (instilled by oral gavage). The chemoprotective response of HEMKLE was evident by inhibition in tumor incidence, mean tumor volume, mean tumor burden, total number of tumors, and tumor size in Group IV (HEMKLE + DMBA/TPA) when compared to Group II (DMBA/TPA). HEMKLE administration also decreased the reactive oxygen species (ROS) and lipid peroxidation (LPO) levels and increased the antioxidants enzyme activities in Group IV (HEMKLE + DMBA/TPA) when compared to Group II (DMBA/TPA) that suggests its antioxidant potential. HEMKLE administration also increased the mRNA and protein expression of caspase-9 and caspase-3 and decreased the mRNA and protein expression of Bcl-2 in Group IV (HEMKLE + DMBA/TPA) when compared to Group II (DMBA/TPA) that suggest its apoptosis-inducing effect on DMBA/TPA induced skin carcinogenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Mice; Murraya; Plant Extracts; Plant Leaves; Skin Neoplasms
PubMed: 32580686
DOI: 10.1024/0300-9831/a000660