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Cancer Science Oct 2019Delphinidin, one of the main anthocyanidins, has potent anti-cancer properties. In this study, we investigated the effect of delphinidin on 1-methyl-1-nitrosourea...
Delphinidin, one of the main anthocyanidins, has potent anti-cancer properties. In this study, we investigated the effect of delphinidin on 1-methyl-1-nitrosourea (MNU)-induced breast carcinogenesis on rats and the mechanism of delphinidin via negative regulation of the HOTAIR/microRNA-34a axis. We found administration of delphinidin could effectively suppress MNU-induced mammal breast carcinogenesis. Delphinidin downregulated the level of HOTAIR and upregulated miR-34a in breast carcinogenesis. Western blot analysis confirmed that delphinidin treatment can significantly decrease the expression of β-catenin, glycogen synthase kinase-3β (Gsk3β), c-Myc, cyclin-D1, and matrix metalloproteinase-7(MMP-7) expression in breast cancer cells, and inhibition of miR-34a significantly reduced the effect of delphinidin on c-Myc, cyclin-D1, and MMP-7. HOTAIR overexpression also blocked the effect of delphinidin on miR-34a and the Wnt/β-catenin signaling pathway in MDA-MB-231 cells. RNA immunoprecipitation (RIP) assay and chromatin immunoprecipitation (ChIP) assay results showed that delphinidin upregulated miR-34a by inhibiting HOTAIR, coupled with enhancement of the zeste homolog 2 (EZH2) and histone H3 Lys27 trimethylation (H3K27me3). This study indicated that delphinidin may potentially suppress breast carcinogenesis and exert its anti-cancer effect through the HOTAIR/miR-34a axis. These findings provided new evidence for the use of delphinidin in preventing breast carcinogenesis.
Topics: Animals; Anthocyanins; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enhancer of Zeste Homolog 2 Protein; Female; Gene Expression Regulation, Neoplastic; Histones; Humans; Methylnitrosourea; MicroRNAs; RNA, Long Noncoding; Rats; Wnt Signaling Pathway; Xenograft Model Antitumor Assays
PubMed: 31325197
DOI: 10.1111/cas.14133 -
Scientific Reports Jan 2021We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary...
We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary experiment involving 5 mini-pig cases to determine the appropriate concentration of MNU, the vitreous cavity of each eye was filled with 4, 8, 10, 12, or 16 mg/mL MNU for 10 min, which was then replaced with a balanced salt solution. Multimodal examinations including spectral-domain optical coherence tomography (OCT) images and full-field electroretinography (ffERG) were obtained at baseline and week 2, week 6, and week 12. The retinal degeneration was classified according to the amplitudes of a dark adaptive (DA) 10.0 a-wave amplitude. The degree of moderate retinal degeneration was defined as DA 10.0 a-wave amplitude ≥ 10% and < 60% of baseline amplitude. The degree of severe degeneration was defined as DA 10.0 a-wave amplitude < 10% of baseline amplitude, noise, or flat signal. Hematoxylin and eosin staining and immunohistochemistry were performed at week 12. The main experiments were conducted first with 10 cases of 5 mg/mL and later with 13 cases of 10 mg/mL. In the preliminary experiment, degree of outer retinal degeneration increased with MNU concentration. Use of 4, 8, 10, 12, and 16 mg/mL MNU showed no, moderate, severe, severe, and atrophic changes, respectively. In the main experiments, there were 9 cases of moderate retinal degeneration and 1 case of severe degeneration in 5 mg/mL MNU group. Two cases of moderate degeneration and 11 of severe degeneration were recorded in 10 mg/mL group. Mean thickness of total retina, inner nuclear layer, and outer nuclear layer decreased at week 2 in both groups. The mean amplitudes on ffERG decreased at week 2. The ffERG and OCT findings did not change from week 2 to week 6 or week 12. The results of staining supported those of ffERG and OCT. Temporal MNU loading in a vitrectomized pig-eye model induced customized outer retinal degeneration with changing the concentration of MNU.
Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroretinography; Intravitreal Injections; Methylnitrosourea; Retinal Degeneration; Swine; Swine, Miniature; Tomography, Optical Coherence; Vitrectomy
PubMed: 33420119
DOI: 10.1038/s41598-020-79437-1 -
In Vivo (Athens, Greece) 2018Physical exercise is increasingly considered by many authors to be a factor reducing the risk of cancer development and premature cancer-related death. Data indicate...
BACKGROUND/AIM
Physical exercise is increasingly considered by many authors to be a factor reducing the risk of cancer development and premature cancer-related death. Data indicate higher cure rates and longer times of survival in cancer patients who regularly exercise.
MATERIALS AND METHODS
A total of 50 female Sprague-Dawley rats were used in the experiment. Animals at 1 month of age were intraperitoneally injected with N-methyl-N-nitrosourea. Three months following drug administration, rats underwent supervised physical training. The animals were divided into four groups: control untrained group and 3 groups trained with different intensities - i.e. low, moderate and high. Routine histopathological examination of tumors was performed and mitotic activity was assessed by immunohistochemical expression of the Ki-67 antigen.
RESULTS
Ki-67 antigen expression was observed in all analyzed tumors. The increase in Ki-67 antigen expression correlated positively with the increase in training intensity.
CONCLUSION
It can be assumed that low-intensity physical training is safe for patients with breast cancer. However, moderate- and high-intensity training may induce tumor cell proliferation worsening patients' prognosis.
Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Exercise; Female; Humans; Immunohistochemistry; Methylnitrosourea; Physical Conditioning, Animal; Rats
PubMed: 29475906
DOI: 10.21873/invivo.11231 -
Carcinogenesis Sep 2017Although regular physical activity is associated with improvement in aerobic capacity and lower breast cancer risk, there are heritable sets of traits that affect...
Although regular physical activity is associated with improvement in aerobic capacity and lower breast cancer risk, there are heritable sets of traits that affect improvement in aerobic capacity in response to physical activity. Although aerobic capacity segregates risk for a number of chronic diseases, the effect of the heritable component on cancer risk has not been evaluated. Therefore, we investigated breast carcinogenesis in rodent models of heritable fitness in the absence of induced physical activity. Female offspring of N:NIH rats selectively bred for low (LIAC) or high (HIAC) inherent aerobic capacity were injected intraperitoneally with 1-methyl-1-nitrosurea (70 mg/kg body wt). At study termination 33 weeks post-carcinogen, cancer incidence (14.0 versus 47.3%; P < 0.001) and multiplicity (0.18 versus 0.85 cancers per rat; P < 0.0001) were significantly decreased in HIAC versus LIAC rats, respectively. HIAC had smaller visceral and subcutaneous body fat depots than LIAC and activity of two proteins that regulated the mammalian target of rapamycin, protein kinase B (Akt), and adenosine monophosphate-activated protein kinase were suppressed and activated, respectively, in HIAC. Although many factors distinguish between HIAC and LIAC, it appears that the protective effect of HIAC against breast carcinogenesis is mediated, at least in part, via alterations in core metabolic signaling pathways deregulated in the majority of human breast cancers.
Topics: AMP-Activated Protein Kinases; Animals; Biomarkers, Tumor; Carcinogenesis; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Physical Conditioning, Animal; Proto-Oncogene Proteins c-akt; Rats; Risk Factors; TOR Serine-Threonine Kinases
PubMed: 28911004
DOI: 10.1093/carcin/bgx066 -
Analytical Chemistry Nov 2022Apurinic/apyrimidinic (AP) sites, that is, abasic sites, are among the most frequently induced DNA lesions. Spontaneous or DNA glycosylase-mediated β-elimination of the...
Apurinic/apyrimidinic (AP) sites, that is, abasic sites, are among the most frequently induced DNA lesions. Spontaneous or DNA glycosylase-mediated β-elimination of the 3'-phosphoryl group can lead to strand cleavages at AP sites to yield a highly reactive, electrophilic 3'-phospho-α,β-unsaturated aldehyde (3'-PUA) remnant. The latter can react with amine or thiol groups of biological small molecules, DNA, and proteins to yield various damaged 3'-end products. Considering its high intracellular concentration, glutathione (GSH) may conjugate with 3'-PUA to yield 3-glutathionyl-2,3-dideoxyribose (GS-ddR), which may constitute a significant, yet previously unrecognized endogenous lesion. Here, we developed a liquid chromatography tandem mass spectroscopy method, in combination with the use of a stable isotope-labeled internal standard, to quantify GS-ddR in genomic DNA of cultured human cells. Our results revealed the presence of GS-ddR in the DNA of untreated cells, and its level was augmented in cells upon exposure to an alkylating agent, -methyl--nitrosourea (MNU). In addition, inhibition of AP endonuclease (APE1) led to an elevated level of GS-ddR in the DNA of MNU-treated cells. Together, we reported here, for the first time, the presence of appreciable levels of GS-ddR in cellular DNA, the induction of GS-ddR by a DNA alkylating agent, and the role of APE1 in modulating its level in human cells.
Topics: Humans; Animals; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA Repair; Methylnitrosourea; DNA Damage; DNA; Alkylating Agents; Mammals
PubMed: 36332130
DOI: 10.1021/acs.analchem.2c02003 -
The Prostate Aug 2022There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did...
BACKGROUND
There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did not identify such an effect. We tested the notion of protective effects in a rat model of prostate carcinogenesis that has been predictive of the effects of selenium and vitamin E in randomized clinical trials and a human prostate cancer xenograft model in nude mice and rat prostate tumor cells transplanted in immune-competent syngeneic animals.
METHODS
Prostate cancer was induced in rats with methylnitrosourea and testosterone and tumor incidence was determined. Subcutaneous tumor growth was measured resulting from injected cells isolated from rat prostate cancers grafted in syngeneic animals and from the prostate-specific antigen (PSA)-producing human prostate cancer PC346 xenografted in nude mice. Brewed decaffeinated green tea infusion or caffeinated green tea extract and the same 300 mg/ml concentration of caffeine were provided in drinking water of the rats and nude mice.
RESULTS
Caffeinated green tea extract and caffeine provided in drinking water did not modify the induction of prostate cancer in the rat model compared with control rats. The same drinking water treatments also did not affect the growth and PSA production of PC346 human prostate cancer xenografts in nude mice and the growth of two transplantable rat prostate cancer tumor lines in Wistar Firth rats. Brewed green tea infusion as drinking water did also not affect tumor growth in these xeno- and allograft models.
CONCLUSION
These animal studies with drinking water exposure to green tea and caffeine do not support the idea that green tea is protective against prostate cancer.
Topics: Animals; Caffeine; Carcinogenesis; Disease Models, Animal; Drinking Water; Heterografts; Humans; Male; Mice; Mice, Nude; Plant Extracts; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Rats; Rats, Wistar; Tea
PubMed: 35485427
DOI: 10.1002/pros.24364 -
Breast Cancer (Dove Medical Press) 2021To evaluate the potential therapeutic role of (graviola) fruit and bee venom (BV) against -methylnitrosourea (MNU)-induced breast cancer in pregnant female rats and...
AIM
To evaluate the potential therapeutic role of (graviola) fruit and bee venom (BV) against -methylnitrosourea (MNU)-induced breast cancer in pregnant female rats and complications in the ovaries.
METHODS
A total of 24 female rats were induced with a single dose of MNU (50 mg/kg body weight). After confirmation of positive tumor marker, female rats were placed with the males for mating. The pregnant rats were randomly divided into four groups (n=6): MNU-induced only (group 1), MNU-induced rats and supplemented with 200 mg/kg diet (group 2), MNU-induced and treated with two doses of BV 75 μg/kg (group 3), and MNU-induced and treated with both and BV (group 4).
RESULTS
In group 1, the breast tissue of mothers revealed pronounced cellular hyperplasia and histopathological signs. Also, the ovarian tissue of mothers and their offspring displayed deleterious histological changes. In groups 2 and 4, histopathological signs and cellular hyperplasia markedly disappeared in breast tissue. However, the histopathological signs induced by MNU in the ovarian tissue reversed to normal in groups 2-4. Also in groups 2-4, levels of serum MMP1, NFκB, and TNFα significantly decreased, and serum caspase 3 significantly increased either in mother rats or their offspring compared to the MNU-alone group. Levels of serum MDA significantly decreased; however, levels of serum antioxidants (CAT and SOD) significantly increased in all groups 2-4 compared to MNU-alone group.
CONCLUSION
has a more powerful therapeutic role than BV against MNU-induced breast cancer in rats; however, both have a powerful ameliorative role against ovarian histopathological alterations induced by MNU. Such ameliorative effects of and BV are mainly attributed to their antioxidant, anti-inflammatory, and antiproliferative constituents.
PubMed: 34267553
DOI: 10.2147/BCTT.S306971 -
Investigative Ophthalmology & Visual... Jul 2020N-methyl-N-nitrosourea (MNU) is an alkylating toxicant with potent mutagenic ability. This study was designed to induce apoptosis in lens epithelial cells (LECs) and...
PURPOSE
N-methyl-N-nitrosourea (MNU) is an alkylating toxicant with potent mutagenic ability. This study was designed to induce apoptosis in lens epithelial cells (LECs) and corneal endothelial cells (CECs) via MNU administration. We sought to build ocular disease models of cataract and corneal endothelial decompensation.
METHODS
MNU was delivered into the intraperitoneal cavities of neonatal rats and the anterior chambers of adult rabbits. The MNU-treated animals were then subjected to a series of functional and morphological analyses at various time points.
RESULTS
MNU treatment induced pervasive apoptosis of LECs and CECs. These effects were dose and time dependent. Mature cataracts were found in neonatal rats 3 weeks after MNU treatment. Histological analysis revealed that MNU toxicity induced swelling, vacuolation, and liquefaction in lens fibers of MNU-treated rats. Pentacam examination showed that the average density of rat lens increased significantly after MNU administration. Terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) analysis showed pervasive apoptotic staining in the lenses of MNU-treated rats. In rabbit eyes, intracameral treatment with MNU induced corneal edema and significantly increased central corneal thickness, which peaked at P14. Morphological and immunohistochemical analysis showed that CECs were effectively ablated in the MNU-treated rabbits. The expression of 8-OHdG increased significantly in the cornea of MNU-treated rabbits, compared with vehicle-treated controls.
CONCLUSIONS
MNU is sufficient to induce ocular cell apoptosis in animal models. These models of MNU-induced cataract and corneal endothelial decompensation represent valuable tools for efforts to develop relevant therapies.
Topics: Alkylating Agents; Animals; Apoptosis; Corneal Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Immunohistochemistry; In Situ Nick-End Labeling; Lens Diseases; Methylnitrosourea; Rabbits; Rats; Reproducibility of Results
PubMed: 32721019
DOI: 10.1167/iovs.61.8.38 -
Nutrients Feb 2018Thyroid cancer (TC) is the most common endocrine malignancy without reliable preventive agent. Resveratrol possesses in vitro anti-TC activities; while its effect(s) on...
Thyroid cancer (TC) is the most common endocrine malignancy without reliable preventive agent. Resveratrol possesses in vitro anti-TC activities; while its effect(s) on thyroid tumorigenesis remains unknown. This study aims to address this issue using DEN/MNU/DHPN-induced rat carcinogenesis model. 50 male Sprague-Dawley rats were separated into four groups as Group-1 (5 rats); normally fed; Group-2 (15 rats); DEN/MNU/DHPN treatment only; Group-3 (15 rats) and -4 (15 rats); DEN/MNU/DHPN treatment; followed by resveratrol intragastric (IG) injection and intraperitoneal (IP) injection; respectively; in two-day intervals for 30 weeks. The results revealed that the average resveratrol concentration in thyroid tissues was 1.278 ± 0.419 nmol/g in IG group and 1.752 ± 0.398 nmol/g in IP group. The final body weights of Group-3 and Group-4 were lighter than that ( > 0.05) of Group-1; but heavier than Group-2 ( < 0.05). TC-related lesions (hyperplasia and adenomas) were found in 53.3% of Group-2; 33.3% Group-3 and 26.7% Group-4. Lower serum carcino-embryonic antigen (CEA) and thyroglobulin (Tg) levels; down-regulated expression of IL-6 and cyclooxygenase-2 (COX-2); reduction of NF-κB/p65 nuclear translocation; and elevated IkB expression were found in the thyroid tissues of Group-3 and Group-4 in comparison with that of Group-2. These results demonstrate that IG and IP administered resveratrol efficiently reduces the frequency and severity of DEN/MNU/DHPN-caused TC-related lesions and would be of values in thyroid tumor prevention.
Topics: Adenoma; Animals; Anticarcinogenic Agents; Carcinoembryonic Antigen; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclooxygenase 2; Diethylnitrosamine; Humans; Hyperplasia; Interleukin-6; Male; Methylnitrosourea; NF-KappaB Inhibitor alpha; Nitrosamines; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Time Factors; Transcription Factor RelA
PubMed: 29495605
DOI: 10.3390/nu10030279 -
International Journal of Molecular... Aug 2017The role of deficiency of oxoguanine glycosylase 1 () homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the...
The role of deficiency of oxoguanine glycosylase 1 () homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant allele of the gene () and wild type (Ogg1) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated male mice, but not in DMBDD-administered animals. Furthermore, incidences of lung adenomas were significantly elevated in both males and females as compared with respective control and DMBDD-treated groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered males and females. In addition, in DMBDD-treated male mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated male mice was significantly higher than that of males. Incidence of small intestine adenomas in DMBDD groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis.
Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Butylhydroxybutylnitrosamine; Carcinogenesis; Carcinogens; Carcinoma, Hepatocellular; DNA Glycosylases; Diethylnitrosamine; Female; Liver Neoplasms; Lung Neoplasms; Male; Methylnitrosourea; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nitrosamines
PubMed: 28820464
DOI: 10.3390/ijms18081801