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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 -
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 -
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 -
Molecular Oncology Mar 2024Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1...
Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via the type I interferon pathway in PD-L1-expressing head and neck cancer.
Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB-induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD-L1-expressing HNSCC in the KEYNOTE-048 trial.
PubMed: 38511232
DOI: 10.1002/1878-0261.13633 -
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 -
BioMed Research International 2021The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of extracts on skin carcinogenesis. Female Swiss albino mice were divided...
The aim of this work is to evaluate the antitumor effect mediated by the proteasome inhibitors of extracts on skin carcinogenesis. Female Swiss albino mice were divided into five groups depending on the combination of skin cancer-inducing 7,12-dimethylbenz(a)anthracene (DMBA) and extract of treatments. Histology of the affected skin and measurement of proteasome activity were performed to demonstrate the effect of on mice. The identification of the molecules responsible for this inhibitory activity was carried out through the docking studies. The results showed that extracts inhibit the development of papilloma in mice. Therefore, the best chemopreventive action of was observed on mice in which extract treatment was performed before and after the induction of skin carcinogenesis. It was revealed that the ingestion of extracts delays the formation of skin papillomas in animals and simultaneously decreases the size and number of papillomas, which is also reflected on the skin histology of the mice treated. Structure-activity relationship information obtained from component of particularly tomentosin, inuviscolide, and isocosticacid demonstrated that distinct bonding modes in , , and subunits determine its selectivity and potent inhibition for subunit.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Caco-2 Cells; Chymotrypsin; Drug Evaluation, Preclinical; Female; Humans; Inula; Mice; Molecular Docking Simulation; Papilloma; Plant Extracts; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Skin Neoplasms; Toxicity Tests
PubMed: 33855081
DOI: 10.1155/2021/6687589 -
Veterinary Medicine and Science Sep 2021Newly, chemo-preventive technique might be a hopeful advancement in developing countries for treating cancers with the aid of toxic less natural based constituents....
BACKGROUND
Newly, chemo-preventive technique might be a hopeful advancement in developing countries for treating cancers with the aid of toxic less natural based constituents. Malignancy urges to augment effectual chemo-preventive agents that are look forward to suppress the tumours which may be stimulated by chewing and smoking of tobacco and over alcohol consumption related with the high prevalence of human oral cancer (OC) patients.
METHODS
In the present research, we examined to assess antioxidants, lipid peroxidation (LPO) and detoxification enzymes levels of anticancer activity of mangiferin on 0.5% 7.12-dimethylbenz[a]anthracene (DMBA) provoked hamster cheek pouch carcinoma (HCPC). OC on hamster buccal pouch (HBP) was incited by DMBA treatment for thrice per week for over 14 weeks.
RESULTS
100% well defined OC establishment with body weight (bw), tumour burden (TB), antioxidant, LPO and liver marker enzymes and also histological changes were observed on DMBA-challenged buccal pouch carcinoma (BPC) in hamsters. Orally treated mangiferin at an effective dosage of 50 mg/kg bw, to DMBA painted hamsters were significantly averted the body weight, succession of tumour, the biochemical as well as histopathological changes.
CONCLUSION
Findings of this work clearly suggest that the anti-carcinoma effect of mangiferin possesses the modulator effects on potent antioxidant, anti-LPO and detoxification agents to expel the metabolites of malignant cells, on DMBA-provoked BPC in hamsters.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Cricetinae; Humans; Mesocricetus; Mouth Neoplasms; Xanthones
PubMed: 33949808
DOI: 10.1002/vms3.500 -
BMC Complementary and Alternative... Sep 2019Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its...
BACKGROUND
Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved.
METHODS
Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin.
RESULTS
With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis.
CONCLUSIONS
Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Carcinogenesis; Carcinogens; Female; Furans; Kidney; Lactones; Liver; Mice; Mice, Inbred ICR; Signal Transduction; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate
PubMed: 31481122
DOI: 10.1186/s12906-019-2650-1