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Scientific Reports Mar 2022Imbalanced glucose tolerance and insulin resistance remain important as high cancer risk factors. Metformin administration to diabetic patients may be associated with a...
Imbalanced glucose tolerance and insulin resistance remain important as high cancer risk factors. Metformin administration to diabetic patients may be associated with a reduced risk of malignancy. The combined effects of the hormone melatonin and metformin in oncology practice have shown positive results. The relevance of our study is to find out the role of specific biomarkers of lysosome destruction and oxidative stress data in carcinogenesis models. The present study was designed to investigate the comparative synergic effect of peroral antidiabetic metformin (MF) and pineal hormone melatonin (MEL) administered alone and in combination in two different rat's models of mammary tumour proliferation in vivo (N-methyl-N-nitrosourea, NMU or 7,12-dimethylbenz[a]anthracene, DMBA). We have studied the processes of lysosomal destruction (alanyl aminopeptidase AAP, leucyl aminopeptidase LAP, acid phosphatase AcP, β-N-acetylglucosaminidase NAG, β-galactosidase β-GD and β-glucuronidase β-GR) caused by evaluated oxidative stress in three types of tissues (liver, heart, and spleen) in female Sprague-Dawley rats fed a high-fat diet (10% of total fat: 2.5% from lard and 7.5% from palm olein). Our results revealed an increase in the activity of the studied lysosomal enzymes and their expression in a tissue-specific manner depending on the type of chemical agent (NMU or DMBA). MANOVA tests in our study confirmed the influence of the three main factors, type of tissue, chemical impact, and chemopreventive agents, and the combinations of these factors on the lysosomal activity induced during the process of cancerogenesis. The development and induction of the carcinogenesis process in the different rat models with the high-fat diet impact were also accompanied by initiation of free-radical oxidation processes, which we studied at the initial (estimated by the level of diene conjugates) and final (TBARS products) stages of this process. The combined effects of MEL and MF for the two models of carcinogenesis at high-fat diet impact for AAP, LAP, and AcP showed a significant synergistic effect when they impact together when compared with the effects of one substance alone (either MEL or MF) in the breast cancer model experiments. Synergistic effects of limiting destructive processes of lysosomal functioning β-GD enzyme activity we obtained in experiments with MEL and MF chemoprevention for both models of carcinogenesis for three tissues. The statistical SS test allowed us to draw the following conclusions on the role of each lysosomal parameter analyzed as an integral model: NAG > AcP > β-GD > β-GR > AAP > LAP.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Autophagy; Carcinogenesis; Diet, High-Fat; Female; Humans; Lysosomes; Mammary Neoplasms, Experimental; Melatonin; Metformin; Oxidative Stress; Rats; Rats, Sprague-Dawley
PubMed: 35322049
DOI: 10.1038/s41598-022-08778-w -
The Journal of Investigative Dermatology Sep 2022P2RY6 is highly expressed in skin keratinocytes, but its function in skin diseases is unclear. We use a two-step chemical induction method to induce mouse skin tumor...
P2RY6 is highly expressed in skin keratinocytes, but its function in skin diseases is unclear. We use a two-step chemical induction method to induce mouse skin tumor formation. Multiple in vitro and in vivo assays were used to explore the role of P2RY6 in skin tumors. We report that P2ry6-deficient mice exhibit marked resistance to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papilloma formation compared with wild-type mice. Consistent with these findings, epidermal hyperplasia in response to TPA was suppressed in the P2ry6-knockout or MRS2578 (P2RY6 antagonist)-treated mice. The dramatic decrease in hyperplasia and tumorigenesis due to P2ry6 disruption was associated with the suppression of TPA-induced keratinocyte proliferation and inflammatory reactions. Notably, P2ry6 deletion prevented the TPA-induced increase in YAP nuclear accumulation and its downstream gene expression in an MST/LATS1-dependent manner. On TPA stimulation, enhanced activation of MAPK/extracellular signal‒regulated kinase kinase 1 and β-catenin were also impaired in P2ry6-knockout primary keratinocytes, tumor tissues, or MRS2578-treated HaCaT cells. Moreover, mutual promotion of the YAP and β-catenin signaling pathways was observed in normal skin cells treated with TPA, whereas P2ry6 deletion could inhibit their crosstalk by regulating MAPK/extracellular signal‒regulated kinase kinase 1. Thus, P2RY6 is a critical positive regulator of skin tumorigenesis through the modulation of the Hippo/YAP and Wnt/β-catenin signaling pathways.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Hyperplasia; Keratinocytes; Mice; Receptors, Purinergic P2; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Wnt Signaling Pathway; YAP-Signaling Proteins; beta Catenin
PubMed: 35304248
DOI: 10.1016/j.jid.2022.02.017 -
Journal of Biochemical and Molecular... Jun 2022The objective of this study is to examine the chemopreventive effects of Nerolidol (NER) on hamster buccal pouch carcinogenesis (HBC) induced by...
The objective of this study is to examine the chemopreventive effects of Nerolidol (NER) on hamster buccal pouch carcinogenesis (HBC) induced by 7,12-dimethylbenz(a)anthracene (DMBA) in male golden Syrian hamsters. In this study, oral squamous cell carcinoma was developed in the buccal pouch of an oral painted hamster with 0.5% DMBA in liquid paraffin three times weekly for 12 weeks. To assess DMBA-induced hamster buccal tissue carcinogenesis, biochemical endpoints such as Phase I and II detoxification enzymes, antioxidants, lipid peroxidation (LPO) by-products, and renal function markers, as well as histopathological examinations, were used. Furthermore, the immunohistochemical studies of interleukin-6 were investigated to find the inflammatory link in the HBC carcinogenesis. In our results, DMBA alone exposed hamsters showed 100% tumor growth, altered levels of antioxidants, detoxification agents, LPO, and renal function identifiers as compared to the control hamsters. The outcome in present biochemical, histopathological, and immunohistochemistry studies has been found a reverse in NER-treated hamsters against the tumor. This study concluded that NER modulated the biochemical profiles (antioxidants, detoxification, LPO, and renal function markers) and inhibited tumor development in DMBA induced oral carcinogenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cricetinae; Male; Mouth Neoplasms; Sesquiterpenes
PubMed: 35243731
DOI: 10.1002/jbt.23029 -
Pharmaceutics Feb 2022Oxidative stress and inflammation act on skin squamous cell carcinoma (SSCC) development and progression. Curative therapy for SSCC patients is mainly based on surgical...
Oxidative stress and inflammation act on skin squamous cell carcinoma (SSCC) development and progression. Curative therapy for SSCC patients is mainly based on surgical resection, which can cause various sequelae. Silver ions have in vitro activities over tumor cells, while nimesulide has antioxidant and anti-inflammatory activities. This study aimed to evaluate the effects of a silver(I) complex with nimesulide (AgNMS) incorporated in a sustained release device based on bacterial cellulose membrane, named AgNMS@BCM, on topic SSCC treatment. The antiproliferative effect of AgNMS complex was evaluated in the SCC4, SCC15 and FaDu SCC lines. AgNMS complex activity on exposure of phosphatidylserine (PS) residues and multicaspase activation were evaluated on FaDu cells by flow cytometry. The AgNMS@BCM effects were evaluated in a SSCC model induced by 7,12-dimethylbenzanthracene/12--tetradecanoyl-phorbol-13-acetate (DMBA/TPA) in mice. Toxicity and tumor size were evaluated throughout the study. AgNMS complex showed antiproliferative activity in SCC15 and FaDu lines in low to moderate concentrations (67.3 µM and 107.3 µM, respectively), and induced multicaspase activation on FaDu cells. The AgNMS@BCM did not induce toxicity and reduced tumor size up to 100%. Thus, the application of AgNMS@BCM was effective and safe in SSCC treatment in mice, and can be seen as a potential and safe agent for topic treatment of SSCC in humans.
PubMed: 35214194
DOI: 10.3390/pharmaceutics14020462 -
Molecules (Basel, Switzerland) Jan 2022Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, -aminophosphonates, arylidine...
Investigation of the Anticancer Effect of -Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2()-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect.
Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, -aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one, DMBA, DMBA & -aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one. New -aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with -aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2()-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Caco-2 Cells; Computer Simulation; Drug Evaluation, Preclinical; Female; Fishes; Humans; Mammary Neoplasms, Experimental; Models, Molecular; Molecular Docking Simulation; Molecular Targeted Therapy; Organophosphonates; Plant Extracts; Quinolines; Rats; Thymidylate Synthase
PubMed: 35164019
DOI: 10.3390/molecules27030756 -
International Journal of Molecular... Jan 2022Endocrine-disrupting chemicals (EDCs)-including butyl benzyl phthalate (BBP), perfluorooctanoic acid (PFOA), and zeranol (α-ZAL, referred to as ZAL hereafter)-can...
Endocrine-disrupting chemicals (EDCs)-including butyl benzyl phthalate (BBP), perfluorooctanoic acid (PFOA), and zeranol (α-ZAL, referred to as ZAL hereafter)-can interfere with the endocrine system and produce adverse effects. It remains unclear whether pubertal exposure to low doses of BBP, PFOA, and ZAL has an impact on breast development and tumorigenesis. We exposed female Sprague Dawley rats to BBP, PFOA, or ZAL through gavage for 21 days, starting on day 21, and analyzed their endocrine organs, serum hormones, mammary glands, and transcriptomic profiles of the mammary glands at days 50 and 100. We also conducted a tumorigenesis study for rats treated with PFOA and ZAL using a 7,12-dimethylbenz[a]anthracene (DMBA) model. Our results demonstrated that pubertal exposure to BBP, PFOA, and ZAL affected endocrine organs and serum hormones, and induced phenotypic and transcriptomic changes. The exposure to PFOA + ZAL induced the most phenotypic and transcriptomic changes in the mammary gland. PFOA + ZAL downregulated the expression of genes related to development at day 50, whereas it upregulated genes associated with tumorigenesis at day 100. PFOA + ZAL exposure also decreased rat mammary tumor latency, reduced the overall survival of rats after DMBA challenge, and affected the histopathology of mammary tumors. Therefore, our study suggests that exposure to low doses of EDCs during the pubertal period could induce changes in the endocrine system and mammary gland development in rats. The inhibition of mammary gland development by PFOA + ZAL might increase the risk of developing mammary tumors through activation of signaling pathways associated with tumorigenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Caprylates; Carcinogenesis; Cell Transformation, Neoplastic; Endocrine Disruptors; Female; Fluorocarbons; Hormones; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Phthalic Acids; Rats; Rats, Sprague-Dawley; Zeranol
PubMed: 35163327
DOI: 10.3390/ijms23031398 -
Biomedicine & Pharmacotherapy =... Mar 2022Naturally occurring phytochemicals especially polyphenolic compounds have received increasing attention as chemopreventive agents. The chemopreventive potential of the...
Naturally occurring phytochemicals especially polyphenolic compounds have received increasing attention as chemopreventive agents. The chemopreventive potential of the ethanolic extract of Salvadora persica L. fruits SP, (the arak tree or miswak) on 7,12-dimethylbenz (a) anthracene (DMBA)-induced mammary carcinogenesis in female albino rats was investigated in this work. Ethanolic extract of SP fruits was supplemented to the experimental groups at a concentration of 500 mg/kg body weight for 22 weeks. Administration of SP extract suppressed DMBA-induced mammary carcinogenesis as revealed by incidence of tumors in histological investigation. There was a significant reduction in cell proliferation and an increase in apoptosis with downregulation of estrogen receptor expression in the mammary tissue of SP-treated animals. Additionally, SP extract prevented the oxidative damage induced in breast tissues of DMBA-treated rats. SP treatment also decreased the viability of MCF-7 breast cancer cells and induced early and late apoptosis and induced S cell cycle arrest. The chemo-preventive properties and anticancer effects of SP could be attributed to its anti-oxidative and a high percentage of phenolic compounds and esters which were detected here in the SP fruit extract.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Cell Proliferation; Down-Regulation; Female; Humans; MCF-7 Cells; Mammary Neoplasms, Experimental; Oxidative Stress; Plant Extracts; Random Allocation; Rats; Rats, Wistar; Receptors, Estrogen; Salvadoraceae; Xenograft Model Antitumor Assays
PubMed: 35124384
DOI: 10.1016/j.biopha.2022.112666 -
Scientific Reports Jan 2022Mammary carcinoma, breast cancer, is the most commonly diagnosed cancer type among women. Therefore, potential new technologies for the diagnosis and treatment of the...
Mammary carcinoma, breast cancer, is the most commonly diagnosed cancer type among women. Therefore, potential new technologies for the diagnosis and treatment of the disease are being investigated. One promising technique is microwave applications designed to exploit the inherent dielectric property discrepancy between the malignant and normal tissues. In theory, the anomalies can be characterized by simply measuring the dielectric properties. However, the current measurement technique is error-prone and a single measurement is not accurate enough to detect anomalies with high confidence. This work proposes to classify the rat mammary carcinoma, based on collected large-scale in vivo S[Formula: see text] measurements and corresponding tissue dielectric properties with a circular diffraction antenna. The tissues were classified with high accuracy in a reproducible way by leveraging a learning-based linear classifier. Moreover, the most discriminative S[Formula: see text] measurement was identified, and to our surprise, using the discriminative measurement along with a linear classifier an 86.92% accuracy was achieved. These findings suggest that a narrow band microwave circuitry can support the antenna enabling a low-cost automated microwave diagnostic system.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma; Electric Conductivity; Electrodiagnosis; Female; Machine Learning; Mammary Neoplasms, Experimental; Microwaves; Predictive Value of Tests; Rats, Sprague-Dawley; Reproducibility of Results; Rats
PubMed: 35013545
DOI: 10.1038/s41598-021-03884-7 -
BMC Complementary Medicine and Therapies Dec 2021Despite the considerable advances made in the treatment of cancer, it remains a global threat. Tartrazine (E102) is a synthetic dye widely used in food industries; it...
BACKGROUND
Despite the considerable advances made in the treatment of cancer, it remains a global threat. Tartrazine (E102) is a synthetic dye widely used in food industries; it has recently been shown to induce oxidative stress (a well known risk factor of cancer) in rat tissues. The present work therefore aimed to assess the impact of a regular consumption of tartrazine on the incidence of breast cancer in rats.
METHODS
Forty (40) Wistar rats aged 55 to 60 days were randomly assigned into 5 groups (n = 8) including two groups serving as normal controls and receiving distilled water (NOR) or tartrazine (NOR + TARZ). The three remaining groups were exposed to the carcinogen DMBA (50 mg/kg) and treated for 20 weeks with either distilled water (DMBA), tartrazine 50 mg/kg (DMBA + TARZ) or a natural dye (DMBA + COL). The parameters evaluated were the incidence, morphology and some biomarkers (CA 15-3, estradiol and α-fetoprotein) of breast cancer. The oxidative status and histomorphology of the tumors were also assessed.
RESULTS
A regular intake of tartrazine led to an early incidence of tumors (100% in rats that received TARZ only vs 80% in rats that received DMBA only), with significantly larger tumors (p < 0.001) (mass = 3500 mg/kg and volume = 4 cm). The invasive breast carcinoma observed on the histological sections of the animals of the DMBA + TARZ group was more developed than those of the DMBA group. The increase in serum α-fetoprotein (p < 0.05) and CA 15-3 (p < 0.01) levels corroborate the changes observed in tumors. The presence of oxidative activity in animals of the DMBA + TARZ group was confirmed by a significant decrease (p < 0.001) in the activity of antioxidant enzymes (SOD and catalase) as well as the level of GSH and increase in the level of MDA compared to the rats of the DMBA and NOR groups.
CONCLUSION
Tartrazine therefore appears to be a promoter of DMBA-induced breast tumorigenesis in rats through its oxidative potential. This work encourages further studies on the mechanisms of action of tartrazine (E102) and its limits of use.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biomarkers, Tumor; Carcinogens; Carcinoma; Estradiol; Female; Mammary Neoplasms, Experimental; Mucin-1; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Tartrazine; Tumor Burden; alpha-Fetoproteins
PubMed: 34972512
DOI: 10.1186/s12906-021-03490-0 -
Current Medical Science Dec 2021Autophagy is a programmed cell death procedure, which has essential functions in tumorigenesis. However, its temporal expression and function under different status are...
OBJECTIVE
Autophagy is a programmed cell death procedure, which has essential functions in tumorigenesis. However, its temporal expression and function under different status are yet to be determined. This study aims to investigate the temporal expression of autophagy and its possible function in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal-pouch cancer model (HBPCM).
METHODS
A total of 50 hamster buccal-pouch tumorigenesis models were established by painting DMBA for 4, 8, 10 and 13 weeks. The expression and subcellular localization of LC3, Beclin 1 and Bcl-2 in buccal lesions were evaluated by immunohistochemical staining and Western blotting. DNA damage was observed by immunohistochemical staining of 8-oHdG. The relationship between Beclin 1 and Bcl-2 was analyzed by immunofluorescence colocalization.
RESULTS
The expression levels of LC3 and Beclin 1 associated with autophagy in the experimental buccal pouch of HBPCM were significantly upregulated after 4 weeks (P<0.05), but gradually downregulated after 13 weeks of HBPCM induction. By contrast, the expression level of Bcl-2 was significantly upregulated after 13 weeks. The co-localized regions of Bcl-2 and Beclin 1 peaked after 4 weeks and then decreased gradually. The DNA damage in epithelial cells increased slightly after 4 weeks, and then rapidly decreased over the next 2 months.
CONCLUSION
Autophagy is motivated by a tumor suppressor that diminishes carcinogen-induced DNA damage. However, autophagy is gradually suppressed, which may be attributed to the interaction between Bcl-2 and Beclin 1. This result indicates that the promotion of autophagy may suppress malignant transformation and provide new insights on future potential treatments of HBPCM.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Autophagy; Beclin-1; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cricetinae; Epithelial Cells; Immunohistochemistry; Mouth Neoplasms; Proto-Oncogene Proteins c-bcl-2; Time Factors
PubMed: 34950986
DOI: 10.1007/s11596-021-2472-5