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Molecular Pharmaceutics Sep 2021The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after...
The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion as the water content increased and released 30% of fenretinide after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in ∼30% smaller structures. The depot formed prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.
Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cell Survival; Delayed-Action Preparations; Drug Liberation; Drug Screening Assays, Antitumor; Emulsions; Female; Fenretinide; Humans; Inhibitory Concentration 50; MCF-7 Cells; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Methylnitrosourea; Mice; Rats
PubMed: 34482696
DOI: 10.1021/acs.molpharmaceut.1c00319 -
Food and Chemical Toxicology : An... Oct 2021Phthalates metabolites have been detected in the urine of pregnant and breastfeeding women. Thus, this study evaluated the adverse effects of maternal exposure to a...
Phthalates metabolites have been detected in the urine of pregnant and breastfeeding women. Thus, this study evaluated the adverse effects of maternal exposure to a mixture of six phthalates (Pth mix) on the mammary gland development and carcinogenesis in F1 female offspring. Pregnant female Sprague-Dawley rats were exposed daily to vehicle or Pth mix (35.22% diethyl-phthalate, 21.03% di-(2-ethylhexyl)-phthalate, 14.91% dibutyl-phthalate, 15.10% diisononyl-phthalate, 8.61% diisobutyl-phthalate, and 5.13% benzylbutyl-phthalate) by gavage at 20 μg/kg, 200 μg/kg or 200 mg/kg during gestational day 10 (GD 10) to postnatal day 21 (PND 21). After weaning (PND 22), some female offspring were euthanized for mammary gland analyses while other females received a single dose of N-methyl-N-nitrosourea (MNU, 50 mg/kg) or vehicle and then tumor incidence and multiplicity were recorded until PND 180. Maternal Pth mix exposure increased the number of Ki-67 and progesterone receptor-positive epithelial cells in the mammary gland from Pth mix 200 at μg/kg and 200 mg/kg groups. In addition, tumor incidence and mean number were higher only in Pth mix at 200 mg/kg when compared to the vehicle-treated group, and percentage of tumor-free animals was lower in Pth mix at 200 μg/kg and 200 mg/kg groups. The findings indicate that perinatal Pth mixture exposure increased susceptibility to MNU-induced mammary carcinogenesis in adult F1 female offspring.
Topics: Animal Feed; Animals; Carcinogenesis; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Gene Expression Regulation; Ki-67 Antigen; Mammary Neoplasms, Animal; Methylnitrosourea; Phthalic Acids; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, Progesterone
PubMed: 34428494
DOI: 10.1016/j.fct.2021.112519 -
Drug and Chemical Toxicology Nov 2022() is used in herbal homes in Nigeria to manage breast diseases. We investigated the anti-tumourigenic effects of chloroform extract of (CP) in breast experimental...
() is used in herbal homes in Nigeria to manage breast diseases. We investigated the anti-tumourigenic effects of chloroform extract of (CP) in breast experimental cancer induced by -methyl--nitrosourea (NMU) and benzo-(a)-pyrene (BaP). Fifty-six female rats were assigned into seven equal groups: Group 1 served as control, group 2 received NMU and BaP (50mg/kg, each), groups 3 and 4 received [NMU + BaP] and treated with CP at 50 and 100mg/kg, respectively. Group 5 received CP (100mg/kg), group 6 received [NMU + BaP] and vincristine (0.5 mg/kg), while group 7 received vincristine (0.5 mg/kg). The NMU and BaP (i.p) were dissolved in normal saline and corn oil, respectively. The CP (oral) and vincristine (i.p) were given thrice and twice per week, respectively for 10 weeks. The [NMU + BaP] intoxication significantly decreased body weight gain by 32% while organo-somatic weight of mammary gland increased by 37%. Also, [NMU + BaP] decreased the activities of mammary catalase, glutathione-s-transferase, glutathione peroxidase, superoxide dismutase and total sulphurhydryl by 34%, 31%, 35%, 35% and 33%, respectively. The [NMU + BaP] increased inflammatory and oxidative stress markers; nitrite, lipid peroxidation and myeloperoxidase by 62%, 57% and 361%, respectively. Strong expression of BCL-2, IL-6, COX 2, β-catenin and iNOS in [NMU + BaP]-administered rats were observed. Histology revealed glands with malignant epithelial cells and high nucleocytoplasm in [NMU + BaP] rats. Treatment with CP attenuated inflammation, apoptosis and restored cyto-architecture of mammary gland. Overall, CP abates mammary tumourigenesis by targeting cellular pathways of inflammation and apoptosis.
Topics: Animals; Female; Rats; Benzo(a)pyrene; beta Catenin; Carcinogenesis; Catalase; Chloroform; Cyclooxygenase 2; Glutathione; Glutathione Transferase; Inflammation; Interleukin-6; Methylnitrosourea; Neoplasms; Nitrites; Peroxidase; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Superoxide Dismutase; Vincristine; Fabaceae
PubMed: 34325589
DOI: 10.1080/01480545.2021.1957556 -
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 2021Previous work by our group has demonstrated the value of N-methyl-N-nitrosourea (MNU)-induced corneal endothelial decompensation in animal models. The aim of this study...
PURPOSE
Previous work by our group has demonstrated the value of N-methyl-N-nitrosourea (MNU)-induced corneal endothelial decompensation in animal models. The aim of this study was to investigate the effect of molecular hydrogen (H2) on MNU-induced corneal endothelial cell (CEC) injury and the underlying mechanism.
METHODS
MNU-induced animal models of CEC injury were washed with hydrogen-rich saline (HRS) for 14 days. Immunofluorescence staining, immunohistochemical staining, and corneal endothelial assessment were applied to determine architectural and cellular changes on the corneal endothelium following HRS treatment. MNU-induced cell models of CEC injury were co-cultured with H2. The effect of H2 was examined using morphological and functional assays.
RESULTS
It was shown that MNU could inhibit the proliferation and specific physiological functions of CECs by increasing apoptosis and decreasing the expression of ZO-1 and Na+/K+-ATPase, whereas H2 improved the proliferation and physiological function of CECs by anti-apoptosis. Cell experiments further confirmed that H2 could reverse MNU damage to CECs by decreasing oxidative stress injury, interfering with the NF-κB/NLRP3 pathway and the FOXO3a/p53/p21 pathway.
CONCLUSIONS
This study suggests that topical application of H2 could protect CECs against corneal damage factors through anti-apoptotic effect, reduce the incidence and severity of corneal endothelial decompensation, and maintain corneal transparency.
Topics: Animals; Apoptosis; Cell Count; Cells, Cultured; Corneal Injuries; Disease Models, Animal; Endothelium, Corneal; Hydrogen; Male; Methylnitrosourea; Oxidative Stress; Rabbits; Rats; Transcriptional Activation; Up-Regulation
PubMed: 34196654
DOI: 10.1167/iovs.62.9.2 -
Anti-cancer Drugs Nov 2021The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via β-adrenergic signaling....
The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via β-adrenergic signaling. However, the potential of β-adrenergic signaling blockade to prevent cancer development after exposure to carcinogens has not been investigated, yet. Therefore, in our study, we determined the effect of the β-blocker propranolol on the development and progression of mammary cancer induced in female rats by administration of the chemical carcinogen N-methyl-N-nitrosourea (MNU). The propranolol treatment (20 mg/kg body weight) started 12 days after MNU administration and lasted 10 weeks. We found that both saline and propranolol treatment significantly increased gene expression of the catecholamine-synthesizing enzyme tyrosine hydroxylase, indicating that repeated injection of saline or propranolol-induced stress in these two groups. However, compared to the vehicle-treated group, propranolol slightly delayed the development and moderately reduced the incidence of mammary carcinoma in animals. To evaluate the mechanisms mediating the effect of propranolol on the development of MNU-induced cancer, we investigated several parameters of the tumor microenvironment and found that propranolol increased gene expression of Casp3. Our data indicate that propranolol treatment that starts after exposure to carcinogens might represent a new, useful approach for preventing the development of cancer, especially in stressed individuals. However, the potential efficiency of propranolol treatment for preventing cancer development and progression in individuals exposed to carcinogens needs further investigation.
Topics: Adrenergic beta-Antagonists; Animals; Caspase 3; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Mammary Neoplasms, Experimental; Methylnitrosourea; Phenylethanolamine N-Methyltransferase; Propranolol; Proto-Oncogene Proteins c-fos; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Tumor Microenvironment; Tyrosine 3-Monooxygenase
PubMed: 34145181
DOI: 10.1097/CAD.0000000000001113 -
Scientific Reports Jun 2021This study aimed to investigate the impact of chronic low-level exposure to chemical carcinogens with different modes of action on the cellular response to ionising...
This study aimed to investigate the impact of chronic low-level exposure to chemical carcinogens with different modes of action on the cellular response to ionising radiation. Human lymphoblastoid GM1899A cells were cultured in the presence of 4-nitroquinoline N-oxide (4NQO), N-nitroso-N-methylurea (MNU) and hydrogen peroxide (HO) for up to 6 months at the highest non-(geno)toxic concentration identified in pilot experiments. Acute challenge doses of 1 Gy X-rays were given and chromosome damage (dicentrics, acentric fragments, micronuclei, chromatid gaps/breaks) was scored. Chronic exposure to 20 ng/ml 4NQO, 0.25 μg/ml MNU or 10 μM HO hardly induced dicentrics and did not significantly alter the yield of X-ray-induced dicentrics. Significant levels of acentric fragments were induced by all chemicals, which did not change during long-term exposure. Fragment data in combined treatment samples compared to single treatments were consistent with an additive effect of chemical and radiation exposure. Low level exposure to 4NQO induced micronuclei, the yields of which did not change throughout the 6 month exposure period. As for fragments, micronuclei yields for combined treatments were consistent with an additive effect of chemical and radiation. These results suggest that cellular radiation responses are not affected by long-term low-level chemical exposure.
Topics: 4-Nitroquinoline-1-oxide; Cell Line; Cell Survival; Chromosomes; Humans; Hydrogen Peroxide; Lymphocytes; Methylnitrosourea; Micronucleus Tests; Radiation Dosage; Radiation Tolerance; Time Factors
PubMed: 34135387
DOI: 10.1038/s41598-021-91957-y -
Naunyn-Schmiedeberg's Archives of... Sep 2021Breast cancer is the most common malignancy in women worldwide. Strategies for cancer chemotherapy commonly require the use of combination therapy for better outcomes of... (Comparative Study)
Comparative Study
Breast cancer is the most common malignancy in women worldwide. Strategies for cancer chemotherapy commonly require the use of combination therapy for better outcomes of results. The present work is aimed to evaluate the potential of naringenin and metformin concomitant addition with doxorubicin chemotherapy against experimental breast carcinoma. The antitumor potential of drugs under the study was evaluated against methylnitrosourea (MNU)-induced breast cancer in rats and 4T1 cells-induced orthotopic breast cancer mouse model. Parameters like tumor growth, body weight, survival rate, blood glucose, hematology, and histology were determined. There was a marked reduction in tumor weight and an observed decrease in tumor multiplicity by naringenin and metformin concomitant addition with doxorubicin against MNU-induced breast carcinoma. Likewise, naringenin and metformin with doxorubicin showed a significant reduction of tumor volume and tumor weight (p < 0.01) in 4T1-induced orthotopic mouse model as compared to the same dose of doxorubicin alone, suggesting combination treatment enhanced antitumor activity in vivo. Furthermore, histology of tumor biopsies presented the improved antitumor activity of doxorubicin via increasing tumor necrosis. Hematological parameters, body weight, and survival data presented remarkable safety of combination treatment without compromising efficacy using 50% lower dose of doxorubicin as compared to the large dose of doxorubicin alone. These results demonstrate that naringenin and metformin enhanced the antitumor effect of doxorubicin in animal models of breast carcinoma, and therefore can be useful as an adjunct treatment with doxorubicin to increase its effectiveness at the lower dose level for the treatment of cancer.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Flavanones; Metformin; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Tumor Burden
PubMed: 34125254
DOI: 10.1007/s00210-021-02104-3 -
BMC Molecular and Cell Biology Jun 2021In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with...
BACKGROUND
In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration.
RESULTS
At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level.
CONCLUSION
Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Body Weight; Carcinoma; Computer Simulation; Electrocardiography; Fatty Acids; Female; Heart Rate; Hypoxia-Inducible Factor-Proline Dioxygenases; Ibogaine; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Metabolome; Methylnitrosourea; Neovascularization, Pathologic; Rats, Wistar; Tamoxifen; Rats
PubMed: 34090331
DOI: 10.1186/s12860-021-00371-9 -
Lipids Jul 2021To investigate alterations of lipidomes in the progress of photoreceptor degeneration induced by N-methyl-N-nitrosourea (MNU) in a rat model, retinal lipid molecular...
To investigate alterations of lipidomes in the progress of photoreceptor degeneration induced by N-methyl-N-nitrosourea (MNU) in a rat model, retinal lipid molecular species in adult Sprague-Dawley (SD) rats at 1, 3, and 7 days after MNU administration and age-matched controls were analyzed by the shotgun lipidomics technology. Moreover, total fatty acid levels in retinal, liver, and plasma samples of different groups were determined with gas chromatography. Generally, at day 1, the levels of ethanolamine plasmalogen species in retinas were markedly elevated after treatment with MNU, while the contents of other phospholipids and sphingolipids in the retina were not significantly changed than those of the control group. The compositions of almost all of unsaturated fatty acids in the retina increased significantly at day 1 after MNU administration. At day 7, the MNU treatment group has significant increases in lipid species in the retina. However, the majority of lipids containing docosahexaenoic acid (DHA, 22:6n-3) and docosapentaenoic acid (22:5n-6) declined, especially di-DHA phospholipids were dramatically reduced in the retina. In contrast, similar alterations did not occur in plasma or the liver after MNU treatment. These results suggested that at the early stage of photoreceptor degeneration, lipidome remodeling in the retina might involve protection of photoreceptor from apoptosis and continue their transduction of light. However, at the late stage of photoreceptor apoptosis, increases in comprehensive lipid species occurred, likely due to the myelination of the retina. Finally, the deficiency of DHA in photoreceptor degeneration could exacerbate the influence of myelination on retinal function. We further investigated the effects of unsaturated fatty acids on neuronal apoptosis. The preliminary experiments confirmed our observation from lipidomics analysis that unsaturated fatty acids can protect neurons from apoptosis. Collectively, our study suggests that increased levels of DHA should be protective from photoreceptor degeneration.
Topics: Animals; Apoptosis; Cell Line; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids; Lipid Metabolism; Lipidomics; Lipids; Liver; Male; Methylnitrosourea; Mice; Neurons; Photoreceptor Cells, Vertebrate; Rats, Sprague-Dawley; Retinal Degeneration; Rats
PubMed: 34058794
DOI: 10.1002/lipd.12306