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Human & Experimental Toxicology Jul 2020Cancer continues to be a major cause of mortality globally. Zebrafish present suitable models for studying the mechanisms of genotoxic carcinogens. The aim of this study... (Comparative Study)
Comparative Study
Cancer continues to be a major cause of mortality globally. Zebrafish present suitable models for studying the mechanisms of genotoxic carcinogens. The aim of this study was to investigate the interaction between oxidant-antioxidant status, apoptosis and immunity in zebrafish that were exposed to three different genotoxic carcinogens methylnitrosourea, dimethylbenzanthracene, benzoapyrene and methylnitrosourea + dimethylbenzanthracene starting from early embryogenesis for 30 days. Lipid peroxidation, nitric oxide levels, superoxide dismutase and glutathione--transferase activities and mRNA levels of apoptosis genes , , , and immunity genes , and were evaluated. The disruption of the oxidant-antioxidant balance accompanied by altered expressions of apoptotic and immunity related genes were observed in different levels according to the carcinogen applied. Noteworthy, expressions decreased in all carcinogen-exposed groups. Our results will provide basic data for further carcinogenesis research in zebrafish models.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Apoptosis Regulatory Proteins; Benzo(a)pyrene; Carcinogens; Embryo, Nonmammalian; Glutathione Transferase; Interferon-gamma; Methylnitrosourea; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Superoxide Dismutase; Zebrafish; Zebrafish Proteins
PubMed: 32054343
DOI: 10.1177/0960327120905961 -
Pakistan Journal of Biological Sciences... Jan 2022<b>Background and Objective:</b> For more than a decade, breast cancer has been one of the most common forms of cancer among women around the world. The...
<b>Background and Objective:</b> For more than a decade, breast cancer has been one of the most common forms of cancer among women around the world. The present article aimed to evaluate the protective activity of CEG-AgNPs against DMBA-induced mammary carcinoma. <b>Materials and Methods:</b> In this experimental study, green synthesis and characterization of CEG-AgNPs were carried as well as IC<sub>50</sub> against Mcf7 cell line and LD<sub>50</sub> on mice were evaluated. A total of 24 adult albino mice were divided into four groups six rats in each. Group I was given an equal amount of distilled water, group II was received 80 mg kg<sup></sup><sup>1</sup> b.wt., DMBA for 4 weeks, groups III and IV were treated with CEG-AgNPs (28.1 and 70.25 mg kg<sup></sup><sup>1</sup>) from the 5th week of DMBA administration for 4 weeks, respectively. <b>Results:</b> CEG-AgNPs were approximately 42.32±9.52 nm with a negative zeta potential of -17.44. It is IC<sub>50</sub> against the Mcf7 cell line and LD<sub>50</sub> is equal to 82.76 μg mL<sup></sup><sup>1</sup> and 1405 mg kg<sup></sup><sup>1</sup> b.wt., A significant normalization in plasma ALT, AST, AST and LDH as well as mammary MDA, TNF-α, IL-6, P53, SOD, GPx and GSH levels have been observed in CEG-AgNPs treated mice. Oral CEG-AgNPs administration has suppressed VEGF-C gene expression in DMBA-treated mice. <b>Conclusion:</b> The present results, biochemical, histological and MRI results showed that CEG-AgNPs have potent anticancer activity against DMBA-induced mammary carcinoma in mice by inducing the biosynthesizes of antioxidant biomarkers and suppression of cytokines gene expression.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Carcinoma; Cytokines; Female; Humans; Mammary Neoplasms, Experimental; Mice; Rats
PubMed: 36098183
DOI: 10.3923/pjbs.2022.485.494 -
The Journal of Nutritional Biochemistry Mar 2021The aim of this study was to investigate the protective effects of pomegranate extract and tangeretin alone or in combination in DMBA-induced rat breast cancer model. A...
The aim of this study was to investigate the protective effects of pomegranate extract and tangeretin alone or in combination in DMBA-induced rat breast cancer model. A total of 68 female rats were randomly divided into 8 groups. The first 4 groups were designed as controls for cancer and treatment groups, and the control groups were composed of only control (C), Pomegranate (P), Tangeretin (T), and Pomegranate+Tangeretin (P+T) groups. The other four groups were designed as cancer and treatment groups and were composed of DMBA (D) and DMBA+Pomegranate (D+P), DMBA+Tangeretin (D+T), DMBA+Pomegranate+Tangeretin (D+P+T) groups. Tumor markers and angiogenesis parameters were studied from plasma samples obtained from rats. Histopathological, immunohistochemical, and TUNEL analyses and expressions of proteins affecting apoptosis and cell cycle were determined in breast tissue samples. In the DMBA group, plasma CA15-3, CEA, VEGF, MMP-9, and NF-κB levels were significantly increased compared to the controls, but significant decreases were observed in these parameters except MMP-9 in the treatment groups. It was observed that p53 and Bax expressions significantly increased in both D+P and D+P+T groups compared to the DMBA group, and these findings were supported by Tunel and immunohistochemical findings. Cyclin D1 expressions were found to be significantly decreased only in the D+T group and supported by TUNEL and immunohistochemical findings. Immunohistochemical ER-α and Ki-67 immune reactivities were significantly decreased in all treatment groups compared to the DMBA group. Our results showed that combined application of pomegranate extract and tangeretin may be more beneficial in preventing breast cancer development.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Carcinogens; Chemoprevention; Drug Combinations; Estrogen Receptor alpha; Female; Flavones; Ki-67 Antigen; Mammary Neoplasms, Experimental; NF-kappa B; Plant Extracts; Pomegranate; Rats; Rats, Sprague-Dawley; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
PubMed: 33326843
DOI: 10.1016/j.jnutbio.2020.108566 -
Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer.Journal of Mammary Gland Biology and... Jun 2022Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well... (Review)
Review
Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer. They develop mammary tumors with comparable histopathology to humans and exhibit differences in resistance or susceptibility to mammary cancer depending on strain. While some rat strains (e.g., Sprague-Dawley) readily form mammary tumors following treatment with the chemical carcinogen, 7,12-dimethylbenz[a]-anthracene (DMBA), other strains (e.g., Copenhagen) are resistant to DMBA-induced mammary carcinogenesis. Genetic linkage in inbred strains has identified strain-specific quantitative trait loci (QTLs) affecting mammary tumors, via mechanisms that act together to promote or attenuate, and include 24 QTLs controlling the outcome of chemical induction, 10 QTLs controlling the outcome of estrogen induction, and 4 QTLs controlling the outcome of irradiation induction. Moreover, and based on shared factors affecting mammary cancer etiopathogenesis between rats and humans, including orthologous risk regions between both species, rats have served as useful models for identifying methods for breast cancer prediction and treatment. These studies in rats, combined with alternative animal models that more closely mimic advanced stages of breast cancer and/or human lifestyles, will further improve our understanding of this complex disease.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Breast Neoplasms; Carcinogens; Estrogens; Female; Humans; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Quantitative Trait Loci; Rats; Rats, Sprague-Dawley
PubMed: 35904679
DOI: 10.1007/s10911-022-09522-w -
Methods in Cell Biology 2022Skin squamous cell carcinoma (skin SCC) is the most frequently occurring cancer. Skin is the first line of defense that provides protection from the external...
Skin squamous cell carcinoma (skin SCC) is the most frequently occurring cancer. Skin is the first line of defense that provides protection from the external environment. Skin consists of epidermis, dermis, and hypodermis. The epidermis comprises of inter-follicular epidermis, hair follicles, sebaceous glands, and sweat glands. Stem cells within these epidermal compartments play crucial role in epidermal regeneration and repair. Various factors such as higher exposure to ultraviolet light (UV) of sun, genetic predisposition, exposure to carcinogens, etc. that give rise to skin cancer. Within the skin SCC, there exists a pool of cancer stem cells (CSCs) that are highly quiescent with self-renewal capacity. Further, isolation and molecular characterization of CSCs would enable to unravel mechanism involved in tumor progression, metastasis, relapse, and resistance to chemotherapeutic agents. To understand the sequential events of carcinogenesis, the two-stage skin carcinogenesis murine model is proposed, which employs the topical application of a chemical carcinogen, DMBA that causes several activating mutations occurring in the genes responsible for cell proliferation and growth. Further, initiation is followed by tumor promotion, which is induced by repeated application of tumor-promoting agent, TPA, which fixes the activating mutations resulting in the formation of a benign papilloma. Subsequently, papilloma further progresses to highly malignant SCC. Here, using the two-stage skin carcinogenesis murine model, we provide a detailed protocol for the isolation of CSCs from murine skin SCC. FACS sorting of CSCs is followed by assays such as invitro-spheroid assay, in vivo-tumorigenesis-limiting dilution and in vivo-tumorigenesis-serial transplantation assay and expression profiling.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Disease Models, Animal; Humans; Mice; Neoplastic Stem Cells; Papilloma; Skin Neoplasms; Tetradecanoylphorbol Acetate
PubMed: 35953206
DOI: 10.1016/bs.mcb.2022.06.002 -
Carcinogenesis Jul 2020Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity...
Previous studies demonstrate that the heavy metal cadmium and the metalloid arsenite activate estrogen receptor-alpha in breast cancer cells by forming a high-affinity complex with the ligand-binding domain of the receptor and that environmentally relevant doses of cadmium have estrogen-like activity in vivo. The present study showed that in estrogen-receptor positive cells, arsenite and cadmium increased the global expression of estrogen-responsive genes and that an environmentally relevant dose of arsenite also had estrogen-like activity in vivo. Similar to estrogens, exposure of ovariectomized animals to arsenite induced the expression of the progesterone receptor, GREB1, and c-fos in the mammary gland and the expression of complement C3, c-fos, and cyclin D1 in the uterus and the increase was blocked by the antiestrogen ICI-182,780. When virgin female animals were fed a diet, that mimics exposure to either arsenite or cadmium, and challenged with the chemical carcinogen dimethylbenzanthracene, there was an increase in the incidence of mammary tumors and a decrease in the time to tumor onset, but no difference in the total number of tumors, tumor multiplicity, or total tumor volume. Together with published results, these data showed that environmentally relevant amounts of arsenite and cadmium had estrogen-like activity in vivo and promoted mammary tumorigenesis.
Topics: Animals; Arsenites; Benz(a)Anthracenes; Cadmium; Carcinogens; Cyclin D1; Estrogen Receptor alpha; Estrogens; Female; Humans; MCF-7 Cells; Mammary Glands, Human; Mammary Neoplasms, Animal; Neoplasm Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptors, Progesterone
PubMed: 31646340
DOI: 10.1093/carcin/bgz176 -
Journal of Biochemical and Molecular... Oct 2022Breast cancer is the primary cause of cancer-related death in females, wherein increased mortality of breast cancer patients is recorded worldwide. Zingiberene is a...
Breast cancer is the primary cause of cancer-related death in females, wherein increased mortality of breast cancer patients is recorded worldwide. Zingiberene is a monocyclic sesquiterpene from the ginger plant and has many pharmacological benefits. In this exploration, we assessed the anticancer actions of Zingiberene against the 7,12-dimethylbenz(a)anthracene (DMBA)-stimulated mammary carcinogenesis in rats and MDA-MB-231 cells. Breast cancer was induced in the Female Sprague-Dawley rats through the 25 mg/kg of DMBA in 0.5 ml of corn oil and then treated with 20 and 40 mg/kg of Zingiberene, respectively. The body weight of animals and tumor volume was measured. Hematological parameters, transaminases, lipid profile, lipid peroxidation, and antioxidants status were scrutinized using standard techniques. The estrogen receptor-α and inflammatory markers were inspected by using respective assay kits. Histological damage scores were determined. In vitro experiments were conducted to scrutinize Zingiberene's effect on cell viability and apoptotic cell death in MDA-MB-231 cells. Zingiberene substantially modulated the DMBA-stimulated physiological and hematological changes and decreased the transaminases, and lipid peroxidation in the DMBA-stimulated animals. Zingiberene also elevated the antioxidant level and suppressed the inflammatory markers. Histological study revealed the protective effects of Zingiberene. The viability of MDA-MB-231 cells was noticeably diminished by the Zingiberene, thus inducing apoptotic cell death. Overall, our findings reliably proved the anticancer potential of Zingiberene against the DMBA-stimulated mammary tumorigenesis, and it could be a promising chemotherapeutic agent.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Antioxidants; Carcinogens; Corn Oil; Female; Mammary Neoplasms, Experimental; Monocyclic Sesquiterpenes; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Transaminases
PubMed: 35698847
DOI: 10.1002/jbt.23146 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Jul 2023The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were...
The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.
Topics: Rats; Female; Animals; Rats, Sprague-Dawley; bcl-2-Associated X Protein; Vascular Endothelial Growth Factor A; Caspase 3; Vascular Endothelial Growth Factor Receptor-2; Fibroblast Growth Factor 2; Proto-Oncogene Proteins c-bcl-2; 9,10-Dimethyl-1,2-benzanthracene; Precancerous Conditions; Hyperplasia; Receptors, Chemokine; RNA, Messenger
PubMed: 37474988
DOI: 10.19540/j.cnki.cjcmm.20230227.401 -
Journal of Mammary Gland Biology and... Jun 2021RNAscope is a quantitative in situ gene expression measurement technique that preserves the spatial aspect of intact tissue; thus, allowing for comparison of specific...
RNAscope is a quantitative in situ gene expression measurement technique that preserves the spatial aspect of intact tissue; thus, allowing for comparison of specific cell populations and morphologies. Reliable and accurate measurement of gene expression in tissue is dependent on preserving RNA integrity and the quantitative nature of RNAscope. The purpose of this study was to determine if the quantitative nature of RNAscope was retained following processing and carmine staining of mammary gland whole-mounts, which are commonly used to identify lesions, such as hyperplasia and ductal carcinoma in situ (DCIS). We were concerned that handling and procedures required to visualize microscopic disease lesions might compromise RNA integrity and the robustness of RNAscope. No effect on the quantitative abilities of RNAscope was detected when mammary gland whole-mounts were pre-screened for lesions of interest prior to RNAscope. This was determined in comparison to tissue that had been formalin-fixed and paraffin embedded (FFPE) immediately after collection. The ability to pre-screen whole-mounts allowed unpalpable diseased lesions to be identified without labor-intensive serial sectioning of tissue samples to find diseased tissue. This method is applicable to evaluate mammary gland whole-mounts during normal mammary gland development, function, and disease progression.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Intraductal, Noninfiltrating; Disease Models, Animal; Female; Gene Expression Profiling; Mammary Glands, Animal; Mammary Neoplasms, Experimental; RNA; Rats; Tissue Preservation
PubMed: 33866475
DOI: 10.1007/s10911-021-09484-5 -
Phytomedicine : International Journal... Jan 2021A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell...
BACKGROUND
A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear.
PURPOSE
The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism.
STUDY DESIGN AND METHODS
This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated.
RESULTS
The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes.
CONCLUSION
This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Carcinogens; Cyclooxygenase 2; Drug Eruptions; Female; Gene Expression Regulation; Humans; Keratinocytes; Mice, Inbred ICR; Ornithine Decarboxylase; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Mice
PubMed: 33310310
DOI: 10.1016/j.phymed.2020.153432