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IUBMB Life Feb 2019Phytol (PHY) (3,7,11,15-tetramethylhexadec-2-en-1-ol) exhibits various pharmacological properties including toxicity and cytotoxicity, and exerts antitumor activity....
Phytol (PHY) (3,7,11,15-tetramethylhexadec-2-en-1-ol) exhibits various pharmacological properties including toxicity and cytotoxicity, and exerts antitumor activity. Owing to the urgent need of new pharmaceutical formulations for breast cancer therapy, this study aimed at the evaluation of antitumor activity of PHY in 7,12-dimethylbenzanthracene-cancer-induced animal model. Comet assay was employed to evaluate the cytogenetics, DNA repair, and antigenotoxic activities of PHY in neoplastic (breast) and non-neoplastic rodent cells (bone marrow, lymphocytes, and liver). Additionally, hematological, biochemical, histopathological, and immunohistochemical analyses were carried out in experimental animals. Thirty nonpregnant female mice (n = 5) underwent 7 weeks treatment with 6 mg/kg pro-carcinogen, PHY (4 mg/kg), and cyclophosphamide (25 mg/kg). Induction of cancer was confirmed by histopathology and immunohistochemistry for Ki-67. Results suggest that PHY exhibits low toxicity in comparison with other groups in hematological, biochemical, histopathological, and organ size parameters. Additionally, PHY showed modulatory effects on the pro-carcinogen, and induced genotoxicity and apoptosis in breast cancer cells. Furthermore, it showed a DNA damage repair capacity in mouse lymphocytes. These data indicate that PHY may have the potential as an anticancer candidate in pharmaceutical consumption. © 2018 IUBMB Life, 71(1):200-212, 2019.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Comet Assay; Cyclophosphamide; DNA Damage; DNA Repair; Drug Administration Schedule; Female; Humans; Ki-67 Antigen; Leukocytes, Mononuclear; Locomotion; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Phytol
PubMed: 30394663
DOI: 10.1002/iub.1952 -
Cell Death & Disease Oct 2018Therapeutic targeting of specific genetic changes in cancer has proven to be an effective therapy and the concept of synthetic lethality has emerged....
Therapeutic targeting of specific genetic changes in cancer has proven to be an effective therapy and the concept of synthetic lethality has emerged. CCAAT/enhancer-binding protein-β (C/EBPβ), a basic leucine zipper transcription factor, has important roles in cellular processes including differentiation, inflammation, survival, and energy metabolism. Using a genetically engineered mouse model, we report that the deletion C/EBPβ in pre-existing oncogenic Ha-Ras mouse skin tumors in vivo resulted in rapid tumor regression. Regressing tumors exhibited elevated levels of apoptosis and p53 protein/activity, while adjacent C/EBPβ-deleted skin did not. These results indicate that the deletion of C/EBPβ de-represses p53 in oncogenic Ras tumors but not in normal wild-type Ras keratinocytes, and that C/EBPβ is essential for survival of oncogenic Ras tumors. Co-deletion of C/EBPβ and p53 in oncogenic Ras tumors showed p53 is required for tumor regression and elevated apoptosis. In tumors, loss of a pathway that confers adaptability to a stress phenotype of cancer/tumorigenesis, such as DNA damage, could result in selective tumor cell killing. Our results show that oncogenic Ras tumors display a significant DNA damage/replicative stress phenotype and these tumors have acquired a dependence on C/EBPβ for their survival. RNAseq data analysis of regressing tumors deleted of C/EBPβ indicates a novel interface between p53, type-1 interferon response, and death receptor pathways, which function in concert to produce activation of extrinsic apoptosis pathways. In summary, the deletion of C/EBPβ in oncogenic Ras skin tumors is a synthetic lethal event, making it a promising target for future potential anticancer therapies.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; CCAAT-Enhancer-Binding Protein-beta; Cell Differentiation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genes, Lethal; Keratinocytes; Mice; Mice, Knockout; Receptors, Death Domain; Signal Transduction; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tumor Suppressor Protein p53; ras Proteins
PubMed: 30323292
DOI: 10.1038/s41419-018-1103-y -
Oncology Reports Sep 2018Environmental factors, including 7,12‑dimethylbenz[a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been...
Environmental factors, including 7,12‑dimethylbenz[a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been demonstrated to increase breast cancer susceptibility. Although DMBA‑ and ErbB2‑mediated breast cancers are well‑studied in their respective models, key interactions between environmental and genetic factors on breast cancer risk remain unclear. Therefore, the present study aimed to investigate the effect of DMBA exposure on ErbB2‑mediated mammary tumorigenesis. MMTV‑ErbB2 transgenic mice exposed to DMBA (1 mg) via weekly oral gavage for 6 weeks exhibited significantly enhanced mammary tumor development, as indicated by reduced tumor latency and increased tumor multiplicity compared with control mice. Whole mount analysis of premalignant mammary tissues from 15‑week‑old mice revealed increased ductal elongation and proliferative index in DMBA‑exposed mice. Molecular analyses of premalignant mammary tissues further indicated that DMBA exposure enhanced epidermal growth factor receptor (EGFR)/ErbB2 and estrogen receptor (ER) signaling, which was associated with increased mRNA levels of EGFR/ErbB2 family members and ER‑targeted genes. Furthermore, analysis of tumor karyotypes revealed that DMBA‑exposed tumors displayed more chromosomal alterations compared with control tumors, implicating DMBA‑induced chromosomal instability in tumor promotion in this model. Together, the data suggested that DMBA‑induced deregulation of EGFR/ErbB2‑ER pathways plays a critical role in the enhanced chromosomal instability and promotion of ErbB2‑mediated mammary tumorigenesis. The study highlighted gene‑environment interactions that may increase risk of breast cancer, which is a critical clinical issue.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Carcinogens; Cell Proliferation; Cell Transformation, Neoplastic; Female; Genomic Instability; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Receptor, ErbB-2; Receptors, Estrogen; Tumor Cells, Cultured
PubMed: 30015966
DOI: 10.3892/or.2018.6545 -
Journal of Dermatological Science Sep 2018
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Mice, Knockout; Mice, Nude; Phosphoproteins; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Trans-Activators; Transcription Factors; Tumor Burden; Tumor Suppressor Proteins; Wnt Signaling Pathway
PubMed: 29885760
DOI: 10.1016/j.jdermsci.2018.05.011 -
Nature Cell Biology Jun 2018Tumour cells are subjected to evolutionary selection pressures during progression from initiation to metastasis. We analysed the clonal evolution of squamous skin...
Tumour cells are subjected to evolutionary selection pressures during progression from initiation to metastasis. We analysed the clonal evolution of squamous skin carcinomas induced by DMBA/TPA treatment using the K5CreER-Confetti mouse and stage-specific lineage tracing. We show that benign tumours are polyclonal, but only one population contains the Hras driver mutation. Thus, benign papillomas are monoclonal in origin but recruit neighbouring epithelial cells during growth. Papillomas that never progress to malignancy retain several distinct clones, whereas progression to carcinoma is associated with a clonal sweep. Newly generated clones within carcinomas demonstrate intratumoural invasion and clonal intermixing, often giving rise to metastases containing two or more distinct clones derived from the matched primary tumour. These data demonstrate that late-stage tumour progression and dissemination are governed by evolutionary selection pressures that operate at a multicellular level and, therefore, differ from the clonal events that drive initiation and the benign-malignant transition.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cell Lineage; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Clonal Evolution; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Genes, ras; Genetic Predisposition to Disease; Male; Mice, Transgenic; Mutation; Neoplasms, Experimental; Phenotype; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors; Tumor Burden
PubMed: 29802408
DOI: 10.1038/s41556-018-0109-0 -
BioMed Research International 2018The present study was designed to evaluate the and antitumor effects of hydroethanolic extract on breast cancer. The cytotoxicity of extract was evaluated using...
The present study was designed to evaluate the and antitumor effects of hydroethanolic extract on breast cancer. The cytotoxicity of extract was evaluated using resazurin reduction assay in 9 cell lines. Further, the protective effect of the hydroethanolic extract of stem barks was evaluated on 7,12-dimethylbenz(a)anthracene- (DMBA-) induced breast cancer rat model. Incidence, burden, volume, and histological analysis of mammary tumors were measured. The extract exhibited CC of 100 in MCF-7 cells after 24 h. , no tumors were detected in rats from the control group, while 11 rats out of 12 (91.66%) developed mammary tumors in the DMBA-exposed group receiving only the vehicle. extract significantly ( < 0.01) and in the dose-dependent manner reduced tumor incidence (3 rats out of 12 at the dose of 300 mg/kg), burden [62.1% (150 mg/kg) and 65.8% (300 mg/kg)], and mass. It protected rats against DMBA-induced breast hyperplasia, with an optimal effect at the dose of 300 mg/kg. Taken altogether, these results suggest that the hydroethanolic extract of might contain phytoconstituents endowed with antitumoral properties, which could protect against the breast cancer induced in rats.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Acacia; Animals; Antineoplastic Agents; Breast Neoplasms; Carcinogens; Cell Line; Cell Line, Tumor; Cytotoxins; Fabaceae; Female; Human Umbilical Vein Endothelial Cells; Humans; MCF-7 Cells; Mammary Neoplasms, Experimental; Mice; NIH 3T3 Cells; Phytotherapy; Plant Extracts; Rats; Rats, Wistar
PubMed: 29770327
DOI: 10.1155/2018/2024602 -
Oncology Reports Jun 2018Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential...
Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13‑acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor β-1 (TGF-β1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Cytokines; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Glucosides; Humans; Mice; Phenols; Random Allocation; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 29693192
DOI: 10.3892/or.2018.6381 -
Scientific Reports Apr 2018Hippo signaling pathway is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis and stem cell self-renewal. TAZ...
Hippo signaling pathway is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis and stem cell self-renewal. TAZ (transcriptional coactivator with the PDZ-binding motif) is a key downstream effector of the mammalian Hippo pathway. Here, using a transgenic mouse model with mammary-gland-specific expression of constitutively active TAZ, we found that TAZ induction in mammary epithelial cells was associated with an increase in mammary glandular size, which probably resulted from adipocyte hypertrophy. Consistent with its known oncogenic potential, we observed tumor formation in TAZ transgenic mice after administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA) and demonstrated that tumorigenesis was reliant on the presence of TAZ. Our findings establish a previously unknown roles of TAZ in regulating both mammary gland morphogenesis as well as carcinogen-induced mammary tumor formation.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Carcinogenesis; Cell Proliferation; Cell Transformation, Neoplastic; Epithelial Cells; Female; Hippo Signaling Pathway; Humans; Intracellular Signaling Peptides and Proteins; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Serine-Threonine Kinases; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins
PubMed: 29691438
DOI: 10.1038/s41598-018-24712-5 -
BMC Complementary and Alternative... Apr 2018Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the...
BACKGROUND
Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2) and macrophages. Recently, the extract of Euterpe oleracea (açaí), a fruit that is widely found in the Amazon region, already showed antitumorigenic effects in vitro in human breast cancer cell lines. The present study aimed to investigate the effect of açaí on breast cancer using a chemically DMBA (7,12-dimethylbenzanthracene) experimental model.
METHODS
One day after initiation of treatment with açaí, mammary carcinogenesis was induced in female Wistar rats using a subcutaneous injection of 25 mg/kg of DMBA in the mammary gland. Forty rats were randomized into two groups: treated with 200 mg/kg of either açaí extract or vehicle, via gastric tube for 16 consecutive weeks. After treatment, the tumor was collected for macroscopic, histological and immunohistochemical (VEGF, vascular endothelial growth factor receptor 2 -VEGFR-2, COX-2 and matrix metalloproteinase -MMP-9) analyses; peritoneal fluid was subjected to flow cytometry (F4-80/MAC-2+) and ELISA immunoassay (VEGF, prostaglandin E -PGE and interleukin-10 -IL-10). Heart, liver and kidney samples were collected for histological analysis.
RESULTS
After 16 weeks of induction, the mammary carcinoma was confirmed by macroscopic and histological evaluation. Survival analysis indicates that açaí increased the survival (P = .0002, long-rank test) and reduced the deaths number (P = .0036, Chi-square test). Açaí treatment decreased the number of inflammatory cells and macrophage positive cells (Mac-2 + F4-80+), as well as promoting a reduction in immunostaining of VEGF, VEGFR-2 and COX-2. The açaí group also exhibited lower concentrations of PGE, VEGF and IL-10 compared to the control. The histopathological results of the liver and kidneys showed protective effect of açaí, since in the control group, there was an increase in fibrosis, atypical cells and hemorrhagic microenvironment.
CONCLUSION
The results of this study demonstrated the antiangiogenic and anti-inflammatory potential of açaí, like due to the decreases of the number of activated macrophages, resulting in the inhibition of DMBA carcinogenicity in breast cancer.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Carcinogens; Cell Line, Tumor; Euterpe; Female; Humans; Mammary Neoplasms, Experimental; Plant Extracts; Rats; Rats, Wistar
PubMed: 29609579
DOI: 10.1186/s12906-018-2183-z -
Oncology Reports Apr 2018Low-intensity ultrasound (LIUS) combined with chemotherapy is an innovative modality for cancer treatment, but its effect on orthotopic carcinoma remains unknown. Our...
Low-intensity ultrasound (LIUS) combined with chemotherapy is an innovative modality for cancer treatment, but its effect on orthotopic carcinoma remains unknown. Our previous study revealed that LIUS enhanced the growth inhibitory effects of several chemotherapeutic drugs in nude mice with transplanted tumors. In the present study, we used 7,12-dimethylbenz(alpha)anthracene to induce orthotopic tongue carcinogenesis in hamsters. We used the first-line chemotherapy drug for tongue cancer, carboplatin (CBP) in combination with LIUS to investigate the synergistic effect. The results revealed that LIUS combined with low-dose CBP enhanced the inhibitory effects of CBP on tumor growth, prolonged survival, and did not increase the incidence of side-effects. It also enhanced the inherent DNA damage caused by CBP, suppressed the expression of the DNA repair proteins O6-methylguanine DNA methyltransferase (MGMT) and Chk1, and increased the expression of DNA damage-inducible protein GADD45α. Furthermore, compared with CBP alone, LIUS combined with CBP reduced the expression of cyclin D1 and cyclin B1, induced the expression of caspase-3, cleaved caspase-3, caspase-8, Bax, and Bak, and inhibited the expression of Bcl-2. Examination of clinical samples revealed that MGMT, Chk1, and Gadd45α were higher in OTSCC than in adjacent normal tissue. Hence, our results indicated that LIUS enhanced the ability of low-dose CBP to damage DNA in an orthotopic hamster model of tongue cancer, induced apoptosis, inhibited tumor growth and progression, while it did not increase the toxic side-effects of the drug, suggesting additional clinical benefits for patients treated with the combination of CBP with LIUS.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Carboplatin; Carcinogenesis; Cell Line, Tumor; Combined Modality Therapy; Cricetinae; DNA Damage; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Tongue Neoplasms; Ultrasonography
PubMed: 29436690
DOI: 10.3892/or.2018.6262