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Li, Wenjie, Haiqian Xu, and Cheng Qian. "c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/7407168.
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Background. Adipose tissue-derived mesenchymal stem cells (ASCs) improve the regenerative ability and retention of fat grafts for breast reconstruction in cancer patients following mastectomy. However, ASCs have also been shown to promote breast cancer cell growth and metastasis. For the safety of ASC application, we aimed to identify specific markers for the subpopulation of ASCs that enhance the growth of breast cancer.Methods. ASCs and bone marrow-derived vascular endothelial progenitor cells (EPCs) were isolated from Balb/c mice. c-Kit-positive (c-Kit+) or c-Kit-negative (c-Kit-) ASCs were cocultured with 4T1 breast cancer cells. Orthotropic murine models of 4T1, EPCs + 4T1, and c-Kit+/-ASCs + 4T1/EPCs were established in Balb/c mice.Results. In coculture, c-Kit+ASCs enhanced the viability and proliferation of 4T1 cells and stimulated c-Kit expression and interleukin-3 (IL-3) release. In mouse models, c-Kit+ASCs + 4T1/EPCs coinjection increased the tumor volume and vessel formation. Moreover, IL-3, stromal cell-derived factor-1, and vascular endothelial growth factor A in the c-Kit+ASCs + 4T1/EPCs coinjection group were higher than those in the 4T1, EPCs + 4T1, and c-Kit-ASCs + 4T1/EPCs groups.Conclusions. c-Kit+ASCs may promote breast cancer growth and angiogenesis by a synergistic effect of c-Kit and IL-3. Our findings suggest that c-Kit+subpopulations of ASCs should be eliminated in fat grafts for breast reconstruction of cancer patients following mastectomy.
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Imamura, Mayu, Tiantian Li, Chunning Li, Masayoshi Fujisawa, Naofumi Mukaida, Akihiro Matsukawa, and Teizo Yoshimura. "Crosstalk between Cancer Cells and Fibroblasts for the Production of Monocyte Chemoattractant Protein-1 in the Murine 4T1 Breast Cancer." Current Issues in Molecular Biology 43, no. 3 (October 22, 2021): 1726–40. http://dx.doi.org/10.3390/cimb43030122.
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The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.
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Du, Jia, Yang Sun, Xiu-Feng Wang, Yi-Yu Lu, Qian-Mei Zhou, and Shi-Bing Su. "Establishment of an Experimental Breast Cancer ZHENG Model and Curative Effect Evaluation of Zuo-Jin Wan." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/324732.
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Herbal formulas based on the traditional Chinese medicine (TCM) syndrome (ZHENG) have been used as alternative treatments for breast cancer. However, there is a lack of the experimental animal ZHENG model for the evaluation of the herbal formulas. In this study, we have established 4T1 mouse breast cancer with Liver Fire Invading Stomach Syndrome model (4T1 LFISS mice) and investigated the effects of the herbal formula, Zuo-Jin Wan (ZJW). Our results showed that 4T1 LFISS mice have the features of LFISS including irritability, loss of appetite, yellow urine, chow, and a tail hot. Compared to untreated 4T1 LFISS mice, ZJW significantly reduced tumor weight and volume (P<0.05), although it was weaker than Cisplatin. However, ZJW significantly increased the body weight and food intake of 4T1 LFISS mice and decreased serum ALT, AST, Cr, and BUN levels and ZHENG score (P<0.05), while Cisplatin reduced the food intake, and body weight and increased serum ALT, AST, Cr, and BUN levels in 4T1 LFISS mice. Our study has provided a mouse breast cancer ZHENG model and showed that ZJW suppresses tumor growth and improves LFISS and kidney and liver functions in the 4T1 LFISS mice.
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ABDUL HAFID, SITTI RAHMA, and AMMU KUTTY RADHAKRISHNAN. "ELUCIDATING THE ROLE OF THE SATB1 GENE IN BREAST CANCER CARCINOGENESIS IN THE PRESENCE OR ABSENCE OF TOCOTRIENOL-RICH FRACTION: EVIDENCE FROM A SYNGENEIC MOUSE MODEL OF BREAST CANCER." Malaysian Applied Biology 50, no. 3 (December 31, 2021): 145–61. http://dx.doi.org/10.55230/mabjournal.v50i3.2087.
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Tocotrienols are reported to possess anticancer activities. Recently we showed that the anticancer effects of tocotrienolrich fraction (TRF) may be through inhibition of the special AT-rich sequence-binding protein 1 (SATB1) gene in a syngeneic mouse model of breast cancer (BC). The present study aims to further explore the role of the SATB1 gene in murine BC cells. The expression of the SATB1 gene in the 4T1 murine BC cells was partially knocked down (SATB1-4T1) using the short hairpin RNA (shRNA) technology and these cells were injected into the mammary pads of mice. Control groups were injected with wild-type 4T1 (WT 4T1) cells. When the tumour was palpable, half of the mice in both groups were fed daily with 1 mg TRF and received intraperitoneal injections of dendritic cells pulsed with tumour lysate (DC+TL) once a week for three weeks. The tumour incidence in mice injected with the SATB1-4T1 cells was reduced (p<0.05) and this effect was independent of TRF supplementation. However, in mice injected with WT-4T1, there was inhibition of tumour growth (p<0.05) only in the group fed with TRF. In addition, the expression of S1004A and mutant P53 genes were suppressed in tumours from animals that were injected with the SATB1-4T1 cells, irrespective of TRF supplementation; which was also observed in tumours from mice injected with WT 4T1 cells and fed with TRF. These findings suggest that TRF may work through the SATB1 pathway.
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Hoyos, M. A., T. Calderon, I. Vergara, and J. Garcia-Solé. "New structural and spectroscopic data for eosphorite." Mineralogical Magazine 57, no. 387 (June 1993): 329–36. http://dx.doi.org/10.1180/minmag.1993.057.387.16.
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AbstractX-ray diffraction refinement of the crystal structure of eosphorite has been carried out with reference to the orthorhombic space group Cmca. The structure is similar to that previously described by Hanson (1960), but the standard deviations are improved. Optical absorption and photoluminescence have also been studied for this mineral. Two sharp emission lines, denoted as R1 and R2, superimposed to a broad band (630-750 nm) have been related to the presence of Cr3+ ions. The excitation spectrum of these emissions confirms that the absorption (excitation) bands centred at 431 nm and 585 are related to with 4A2 → 4T1 and 4A2 → 4T2 spin allowed transitions of this ion.
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Morshed, Ramin, Alexander Haddad, Saket Jain, Sabraj Gill, Jordan Spatz, and Manish K. Aghi. "TAMI-06. TUMOR CELL-DERIVED CYTOKINE EXPRESSION CHANGES ASSOCIATED WITH BRAIN METASTASIS IN A SYNGENEIC MOUSE MODEL OF BREAST CANCER." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi199. http://dx.doi.org/10.1093/neuonc/noab196.790.
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Abstract Breast cancer is the most common malignancy in women in the United States, and brain metastases occur in almost a third of patients with metastatic dissemination. Immunoediting is a critical component of metastatic tumor cell elimination, and tumor clones that develop immune-escape mechanisms are associated with progression and metastatic dissemination. We hypothesized that breast cancer brain metastatic cells harbor immunomodulatory cytokine expression changes that promote an immunosuppressive environment to avoid immune cell-mediated elimination. To study this, a syngeneic mouse model of metastatic breast cancer was used. A brain metastatic line derived from the 4T1 breast cancer parental cell line was created by serially selecting brain metastatic populations of cells after intracardiac injection (4T1 BrM). A gene-expression analysis using an 800-gene cancer immunology-specific microarray panel was performed comparing the 4T1 parental and 4T1 BrM lines. 4T1 BrM cells demonstrate gene expression changes promoting immunosuppression including significant upregulation of IL18 and Lgals9 (Galectin-9) and downregulation of CD40, IL2rg, CCL2, and EOMES. When compared to 4T1 parental lines, the 4T1 BrM line demonstrated decreased expression of CCL2 and increased expression of GM-CSF on a cytokine array, corresponding to results obtained from gene expression analysis. These results suggest tumor-intrinsic cytokine expression changes that may mediate an immunosuppressive environment.
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Wang, Bai Bin, Chi Fen Chang, Yan Ru Li, Thanh Nam Chau, and Wein Duo Yang. "Synthesis and Light-Emission Properties of Manganese-Doped Calcium Zirconate Phosphor and Manganese-Doped Strontium Zirconate Phosphor." Applied Mechanics and Materials 234 (November 2012): 1–6. http://dx.doi.org/10.4028/www.scientific.net/amm.234.1.
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This study successfully synthesized manganese-doped calcium zirconate phosphor and manganese-doped strontium zirconate phosphor using the sol-gel method. We employed X-ray powder diffraction and fluorescence spectroscopy to analyze the crystal structure and spectral characteristics of both phosphors. In X-ray powder diffraction analysis, data related to manganese-doped calcium zirconate phosphor and manganese-doped strontium zirconate phosphor were compared using X-ray diffraction comparison software to confirm the crystal structures of both phosphors. The crystal structure of manganese-doped calcium zirconate phosphor was in accordance with orthorhombic perovskites belonging to the Pnma {62} space group. The lattice parameters were a=5.762 Å, b=8.017 Å, and c=5.591 Å; c/a=0.97; volume=258.3 Å3, and density=4.611 g/cm3. The crystal structure of manganese-doped strontium zirconate phosphor conformed to orthorhombic perovskites belonging to the Pnma {62} space group, and the lattice parameters were a=5.818 Å, b=8.204 Å, c=5.797 Å; c/a=0.996; volume=276.7 Å3, and density=5.446 g/cm3. Fluorescence spectroscopy indicated that the primary broadband peak of manganese-doped calcium zirconate phosphor was located at 396.6 nm in the excitation spectrum corresponding to the 4T2(4G)4T1(4P) energy level transition. In the emission spectrum, the primary broadband peak was located at 596.6 nm, corresponding to the 4T2(4D)4T2(4G) energy level transition. For manganese-doped strontium zirconate phosphor, the primary broadband peak was located at 496.6 nm in the excitation spectrum and at 696.6 nm in the emission spectrum, corresponding to the 4T1(4G)4T2(4D) and 4E(4G)4T1(4G) energy level transitions, respectively.
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Yoshimura, Teizo, Kaoru Nakamura, Chunning Li, Masayoshi Fujisawa, Tsuyoshi Shiina, Mayu Imamura, Tiantian Li, Naofumi Mukaida, and Akihiro Matsukawa. "Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer." International Journal of Molecular Sciences 20, no. 24 (December 16, 2019): 6342. http://dx.doi.org/10.3390/ijms20246342.
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We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.
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Pereira, Jonathas Xavier, Sofia Nascimento dos Santos, Thaís Canuto Pereira, Mariana Cabanel, Roger Chammas, Felipe Leite de Oliveira, Emerson Soares Bernardes, and Márcia Cury El-Cheikh. "Galectin-3 Regulates the Expression of Tumor Glycosaminoglycans and Increases the Metastatic Potential of Breast Cancer." Journal of Oncology 2019 (December 17, 2019): 1–15. http://dx.doi.org/10.1155/2019/9827147.
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Galectin-3 (Gal-3) is a multifunctional β-galactoside-binding lectin that once synthesized is expressed in the nucleus, cytoplasm, cell surface, and extracellular environment. Gal-3 plays an important role in breast cancer tumors due to its ability to promote interactions between cell-cell and cell-extracellular matrix (ECM) elements, increasing tumor survival and metastatic dissemination. Still, the mechanism by which Gal-3 interferes with tumor cell migration and metastasis formation is complex and not fully understood. Here, we showed that Gal-3 knockdown increased the migration ability of 4T1 murine breast cancer cells in vitro. Using the 4T1 orthotopic breast cancer spontaneous metastasis mouse model, we demonstrated that 4T1-derived tumors were significantly larger in the presence of Gal-3 (scramble) in comparison with Gal-3 knockdown 4T1-derived tumors. Nevertheless, Gal-3 knockdown 4T1 cells were outnumbered in the bone marrow in comparison with scramble 4T1 cells. Finally, we reported here a decrease in the content of cell-surface syndecan-1 and an increase in the levels of chondroitin sulfate proteoglycans such as versican in Gal-3 knockdown 4T1 cells both in vitro and in vivo. Overall, our findings establish that Gal-3 downregulation during breast cancer progression regulates cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycans (PG), thus enhancing the metastatic potential of tumor cells.
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Emamian, Manouchehr, Akbar Abbaspour, Tina Shahani, Alireza Biglari, and Ali Sharafi. "Non-viral Suicide Gene Therapy: Cytosine Deaminase Gene Directed by VEGF Promoter and 5-fluorocytosine as a Gene Directed Enzyme/prodrug System in Breast Cancer Model." Drug Research 71, no. 07 (June 28, 2021): 395–406. http://dx.doi.org/10.1055/a-1488-6054.
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AbstractThe present study investigated the potential of vascular endothelial growth factor (VEGF) promoter to derive cytosine deaminase (CD) transfected by polyamidoamine (G4-PAMAM) dendrimers to 4T1 murine breast cancer cell line as gene-directed enzyme/prodrug therapy. The VEGF promoter and cytosine deaminase gene were cloned into the pEGFP-N1vector from the genomic DNA of 4T1 and E. coli, respectively. The frequency of transfection for VEGF-CD-pEGFP-N1 and pEGFP-N1- CD treated groups was 35±3 and 36±4, respectively. MTT assay was perform to evaluate the cytotoxic effects of converted 5-flurocytosine on 4T1 cells. Also, the optimal concentration of 5-FC in 4T1 cells transfected by VEGF-CD-pEGFP-N1 plasmid was evaluated. The GFP expression of transfected 4T1 cells by VEGF-CD-pEGFP-N1were observed by fluorescent microscopy and flowcytometry. Results demonstrated that the suicide CD gene was successfully expressed in 4T1 cells determined by RT-PCR and GFP expression. A concentration of 200 μg/ml 5-FC was identified as optimal dose of prodrug. Furthermore, the CD/5-FC enzyme/prodrug system not only demonstrated toxicity on transformed 4T1 cells but also exerted a ‘bystander effect’ determined by MTT assay. The results showed that by 35% transfection with VEGF-CD–pEGFP-N1and CD-pEGFP-N1 plasmids, 80% and 90% inhibition of the cells growth occurred, respectively.
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Van, Bui Hong, Pham Van Ben, Tran Minh Thi, and Hoang Nam Nhat. "Absorption and Radiation Transitions in Mn2+(3d5) Configuration of Mn-Doped ZnS Nanoparticles Synthesized by a Hydrothermal Method." Journal of Materials 2013 (April 21, 2013): 1–9. http://dx.doi.org/10.1155/2013/716452.
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The Mn-doped ZnS nanoparticles with Mn content of 0–15 mol% were synthesized by a hydrothermal method from the solutions Zn(CH3COO)2 0.1 M, Mn(CH3COO)2 0.01 M, and Na2S2O3 0.1 M at 220°C for 15 h. These nanoparticles presented the cubic structure with average particle size about 16 nm. The yellow-orange photoluminescence (PL) band at 586 nm was attributed to the radiation transition of the electrons in 3d5 unfilled shell of Mn2+ ions [4T1(4G)-6A1(6S)] in ZnS matrix. The photoluminescence excitation (PLE) spectra monitored at the yellow-orange band, the absorption spectra also showed the near band edge absorption of 336–349 nm and the characteristic absorption bands of Mn2+(3d5) ions at 392, 430, 463, 468, 492, and 530 nm. These bands should be attributed to the absorption transitions of 3d5 electrons from the ground state 6A1(6S) to the excited states 4E(4D), 4T2(4D), 4A1(4G)-4E(4G), 4T2(4G), and 4T1(4G) of Mn2+ ions. The intensity of PL band and absorption bands of Mn2+(3d5) ions also increased with the Mn content from 0.1 to 9 mol%, but their peak positions were almost unchanged. The PLE spectra showed clearly the energy level splitting of Mn2+ ions in ZnS crystal field and allowed for the calculation of the splitting width between the excited states 4A1(4G), 4E(4G) about of 229 cm−1 (28.6 meV), and the Racah parameters B=559 cm−1, C=3202 cm−1 (γ=C/B=5.7), and the crystal field strength Dq=568 cm−1. The PL spectra with different excitation wavelengths corresponding to absorption transition bands of the PLE spectra allow for the discussion of the indirect and direct excitation mechanisms of Mn2+(3d5) ions in the ZnS crystal.
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Messerli, Shanta M., Amanda M. Schaefer, Yongxian Zhuang, Bohdan J. Soltys, Noah Keime, Jenny Jin, Li Ma, Carleton J. C. Hsia, and W. Keith Miskimins. "Use of Antimetastatic SOD3-Mimetic Albumin as a Primer in Triple Negative Breast Cancer." Journal of Oncology 2019 (February 28, 2019): 1–11. http://dx.doi.org/10.1155/2019/3253696.
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Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.
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Milanizadeh, Sara, Abbas Aliaghaei, and Mohammad Reza Bigdeli. "Neuroprotective Effect of 4T1 and Sertoli Cells Co-Transplantation in Animal Model of Brain Ischemia." International Journal of Basic Science in Medicine 3, no. 3 (October 6, 2018): 133–39. http://dx.doi.org/10.15171/ijbsm.2018.24.
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Aim: Introducing neurotrophic factors are among several new approaches to enhance neural resistance to the ischemic condition. Cancer cells such as 4T1 are one of the strongest cells with high viability in transplanted area. 4T1 cells are invasive breast carcinoma cells derived from spontaneous tumors in mouse Balb/C which their pathologic effects are limited to Balb/C species. Sertoli cells (SCs) can be a proper candidate for increasing transplanted cells survival. These cells not only suppress the immune system, but also secret growth factors. The aim of this study is to evaluate the possible neuroprotective effect of 4T1 transplantation on middle cerebral artery occlusion (MCAO) rat model alone and with SCs co-transplanted. Material and Methods: Rats were divided into five experimental groups: control, sham, SCs, 4T1 and 4T1+SCs treated groups. Cells were transplanted into the right striatum by using stereotaxic surgery. Ischemic surgery was done after five days. 24 hours after reperfusion, neurological severity score, infarct volume, brain edema, and blood-brain barrier permeability were assessed in different areas of the brain including cortex, striatum and piriform cortex-amygdala (Pir-Amy). Results: This study demonstrates that SCs and 4T1 transplantation ameliorate neurological deficits and reduce infarct volume, brain edema and blood-brain barrier permeability compared to the control group. Conclusion: Introducing cancer cell transplantation as a source of neurotrophic factors to enhance neural survival can be a new approach in cell therapy.
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Yeh, Su-Peng, Wen-Jyi Lo, and Chang-Fang Chiu. "Bone Marrow-Derived Mesenchymal Stem Cell Homing to Breast Cancer but Not Colon and Renal Cancer and VEGF-C and VEGF-R3 Play the Key Role in Tumor Homing Effect in the Syngeneic Mice (Balb/c) Model,." Blood 118, no. 21 (November 18, 2011): 3418. http://dx.doi.org/10.1182/blood.v118.21.3418.3418.
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Abstract Abstract 3418 Background Mesenchymal stem cells (MSCs) have the unique ability of homing to tumor tissue. Most of prior studies used xenograft models to demonstrate hMSC homing to human cancer on the immunodeficient mice. This model is far away from clinically relevant condition. It was also unknown whether MSCs target specific or all the tumor types in immunocompotent host as well as the mechanism driving MSCs home to tumor site. Methods Migration assay was done to access the in vitro migration effect of D1 cells (BM-MSCs derived from balb/c mice) in response to 4T1, CT26, and Rag cells (breast cancer, colon cancer, and renal cancer cell line derived from balb/c mice). Firefly luciferase (Luc) stably expressed D1 (D1-Luc) was selected and maintained. 4T1 and CT26 cells were inoculated into 6 weeks balb/c mice. D1-Luc cells were then injected into normal or tumor-bearing balb/c through tail vein at different tumor stage (small tumors and big tumors). Besides, 4T1 and CT26 cells were inoculated into bilateral sides of balb/c mice. After tumor formation, D1-Luc cells were injected locally into one side to see whether the D1-Luc can migrate to the contralateral tumor or not. The in vivo tumor homing was accessed by IVIS (xenogen). Finally, 4T1 and CT26 tumors were excised from the mice to analyze gene expression profile (GEP). Chemokines/cytokines highly expressed on 4T1 but not CT26 were selected for blocking study in vitro and in vivo. Results Both in vitro and in vivo studies showed D1 homing to 4T1 (breast) tumor only but not CT26 (colon) and Rag (renal) tumor. In case of 4T1, D1-Luc homed to all (100%) the tumor-bearing mice though tail vein injection. Besides, D1-Luc cells also home to both big and small 4T1 tumor simultaneously. When D1-Luc injected locally to one side of 4T1-bearing mice, the luciferase activity can be detected at the contralateral 4T1 tumor one hour after injection. In case of CT26, luciferase activity can not be detected on the contralateral CT26 tumor up to 7 days after injection. The GEP study showed VEGF-C, CCL24, CXCL 1/2/7 were highly expressed in 4T1 but not CT26. Blocking the VEGF-C receptor of D1 alone by using neutralizing antibody was sufficient to suppress D1 cells migration toward 4T1 tumor both in vitro and in vivo. The expression of VEGF-C is 100-fold higher in tumor tissue comparing to normal tissues (lung, liver, spleen, and kidney) by using RT-PCR. Conclusions MSCs home to specific tumor only and specific ligand-receptor relationship between MSCs and cancer cells determines the specificity. In this immunocompetent, syngeneic mice model, BM-MSCs homes to breast cancer but not normal tissue via VEGF-C and VEGF-C receptor axis. Our model also provides a good platform to the future development of MSC-based cell therapy. Before starting such a trial in human, it is essential to identify a specific ligand that is highly expressed on tumor (maybe very specific type of tumor) but not normal tissues and the MSCs should have corresponding receptor. This work was supported in part by the research grant from Taiwan National Science Council (NSC-96-3111-B-039-001), and Department of Health, China Medical University Hospital Cancer Research of Excellence (DOH-100-TD-C-111-005). Disclosures: No relevant conflicts of interest to declare.
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Benazic, Sasa, Zana Besser Silconi, Andra Jevtovic, Milena Jurisevic, Jelena Milovanovic, Marina Mijajlovic, Milos Nikolic, et al. "The Zn(S-pr-thiosal)2 complex attenuates murine breast cancer growth by inducing apoptosis and G1/S cell cycle arrest." Future Medicinal Chemistry 12, no. 10 (May 2020): 897–914. http://dx.doi.org/10.4155/fmc-2019-0215.
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Aim: We investigated the antitumor effects of zinc(II) complex with S-propyl thiosalicylic acid [Zn( S-pr-thiosal)2] in 4T1 murine breast cancer model. Results: The Zn( S-pr-thiosal)2 complex reduced primary tumor growth in vivo and induced tumor cell apoptosis. The Zn( S-pr-thiosal)2 complex disrupted the balance between pro- and antiapoptotic Bcl-2 family members in 4T1 cells and induced G1/S cell cycle arrest. The Zn( S-pr-thiosal)2 complex increased the percentage of p16, p21 and p27 positive 4T1 cells. There was a significantly decrease in expression of STAT3 and its targets c-Myc and cyclin D3 in 4T1 cells treated with the Zn( S-pr-thiosal)2 complex thus contributing to G1/S cell cycle arrest and/or apoptosis. Conclusion: Our data suggest that the Zn( S-pr-thiosal)2 complex restricted tumor growth through induction of mitochondrial-driven apoptosis and suppression of cell cycle progression.
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Romli, Firdaus, Nadiah Abu, Faten A. Khorshid, Syed Umar Faruq Syed Najmuddin, Yeap Swee Keong, Nurul Elyani Mohamad, Muhajir Hamid, Noorjahan Banu Alitheen, and Nik Mohd Afizan Nik Abd Rahman. "The Growth Inhibitory Potential and Antimetastatic Effect of Camel Urine on Breast Cancer Cells In Vitro and In Vivo." Integrative Cancer Therapies 16, no. 4 (June 23, 2016): 540–55. http://dx.doi.org/10.1177/1534735416656051.
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Although it may sound unpleasant, camel urine has been consumed extensively for years in the Middle East as it is believed to be able to treat a wide range of diseases such as fever, cold, or even cancer. People usually take it by mixing small drops with camel milk or take it directly. The project aims to study the effects of camel urine in inhibiting the growth potential and metastatic ability of 4T1 cancer cell line in vitro and in vivo. Based on the MTT result, the cytotoxicity of camel urine against 4T1 cell was established, and it was dose-dependent. Additionally, the antimetastatic potential of camel urine was tested by running several assays such as scratch assay, migration and invasion assay, and mouse aortic ring assay with promising results in the ability of camel urine to inhibit metastatic process of the 4T1 cells. In order to fully establish camel urine’s potential, an in vivo study was carried out by treating mice inoculated with 4T1 cells with 2 different doses of camel urine. By the end of the treatment period, the tumor in both treated groups had reduced in size as compared to the control group. Additional assays such as the TUNEL assay, immunophenotyping, cytokine level detection assay, clonogenic assay, and proteome profiler demonstrated the capability of camel urine to reduce and inhibit the metastatic potential of 4T1 cells in vivo. To sum up, further study of anticancer properties of camel urine is justified, as evidenced through the in vitro and in vivo studies carried out. Better results were obtained at higher concentration of camel urine used in vivo. Apart from that, this project has laid out the mechanisms employed by the substance to inhibit the growth and the metastatic process of the 4T1 cell.
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Wang, Chung-Yih, Chun-Yuan Chang, Chun-Yu Wang, Kaili Liu, Chia-Yun Kang, Yi-Jang Lee, and Wei R. Chen. "N-Dihydrogalactochitosan Potentiates the Radiosensitivity of Liver Metastatic Tumor Cells Originated from Murine Breast Tumors." International Journal of Molecular Sciences 20, no. 22 (November 8, 2019): 5581. http://dx.doi.org/10.3390/ijms20225581.
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Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and γ-H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors.
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Rosidah, Rosidah, Poppy Anjelisa Zaitun Hasibuan, Ginda Haro, and Denny Satria. "Cytotoxicity Activity of Ethanol Extract of Andaliman Fruits (Zanthoxylum acanthopodium DC.) towards 4T1 Breast Cancer Cells." Indonesian Journal of Pharmaceutical and Clinical Research 2, no. 2 (December 30, 2019): 31–35. http://dx.doi.org/10.32734/idjpcr.v2i2.3220.
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Breast cancer is one of the world's leading cause of death in women. Due to the resistance of chemotherapeutic agents, there is a continuous need to search of natural products with anticancer activity. The use of natural products is expected to increase the effectiveness and decrease side effect. The purpose of this study was to investigate the anticancer activity of ethanol extract of andaliman fruits (EEAF) towards 4T1 cells. Extracts were prepared by maceration using solvent ethanol 96%. 4T1 cells were grown in culture medium DMEM then given by EEAF and doxorubicin. Cytotoxic test in vitro was done by MTT method [3-(4,5-dimetiltiazol-2-il) -2.5 difeniltetrazolium bromide] which is then analyzed using SPSS 21. The results from this study showed that the cytotoxic results (IC50) after treatment with EEAF and doxorubicin were 54.48 ± 0.22 µg/mL dan 0.80 ± 0.02 µg/mL.Based on the result above, we conclude that EEAF has cytotoxic activity towards 4T1 cancer cells.
Key words: andaliman fruits, Zanthoxylum acanthopodium DC., ethanol extract, breast cancer, 4T1 cell line.
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Nordin, Muhammad Luqman, Arifah Abdul Kadir, Zainul Amiruddin Zakaria, Fauziah Othman, Rasedee Abdullah, and Muhammad Nazrul Hakim Abdullah. "Cytotoxicity and Apoptosis Induction of Ardisia crispa and Its Solvent Partitions against Mus musculus Mammary Carcinoma Cell Line (4T1)." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/9368079.
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This study was conducted to investigate the cytotoxicity and apoptosis effect of A. crispa extract and its solvent partition (ethyl acetate and aqueous extract) against Mus musculus mammary carcinoma cell line (4T1). The normal mouse fibroblast cell line (NIH3T3) was used as comparison for selective cytotoxicity properties. The cytotoxicity evaluation was assessed using MTT assay. AO/PI dual fluorescent staining assay and Annexin V-FITC were used for apoptosis analysis. Results showed that 80% methanol extract from leaves showed most promising antimammary cancer agent with IC50 value of 42.26±1.82 μg/mL and selective index (SI) value of 10.22. Ethyl acetate was cytotoxic for both cancer and normal cell while aqueous extract exhibited poor cytotoxic effect. 4T1 cells labelled with AO/PI and Annexin V-FITC and treated with 80% methanol extract demonstrated that the extract induces apoptosis to 4T1 mammary cancer cells. In conclusion, 80% methanol extract of A. crispa was selectively cytotoxic towards 4T1 cells but less cytotoxic towards NIH3T3 cells and induced the cancerous cells into apoptotic stage as early as 6 hours.
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Nurrachma, Marsya Yonna, Gergorius Gena Maran, Nindya Budiana Putri, Yuni Fajar Esti, Adam Hermawan, Edy Meiyanto, and Riris Istighfari Jenie. "Fingerroot (Boesenbergia pandurata) Extract Inhibits Proliferation and Migration of 4T1 Metastatic Breast Cancer Cells." Indonesian Journal of Cancer Chemoprevention 11, no. 3 (November 18, 2020): 103. http://dx.doi.org/10.14499/indonesianjcanchemoprev11iss3pp103-114.
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Fingerroot (Boesenbergia pandurata) is an Indonesian herb, with anti-proliferation and anti-migratory effects against several cancer cells. This study aims to investigate the anticancer property of Fingerroot Extract (FE) in combination with doxorubicin (Dox) against 4T1, a metastatic breast cancer cell lines. FE was prepared by 96% ethanol maceration and characterized by thin-layer chromatography analysis. FE was subjected to a cytotoxicity test with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay alone or in combination with 10 nM Dox against 4T1 cells. Cytotoxic effect was then confirmed by measure reactive oxygen species (ROS) intracellular level using 2’,7’-dichloroflourescin diacetate (DCFDA)-staining flow cytometry-based assay. The anti-migratory effect was observed using scratch wound healing assay and gelatin zymography to investigate matrix metalloproteinase (MMP)-9 expression. FE showed a cytotoxic effect with an inhibitory concentration 50 (IC50) value of 25.5±3.9 μg/mL and performed an improved effect in combination with 10 nM Dox. A single treatment of FE decreased ROS intracellular level, while in combination with Dox, FE increased the ROS intracellular level. Further, at 42 h observation, FE and its combination with Dox inhibited the migration of 4T1 cells with % closure of 82.6 and 82.5, respectively, correlates with a significant decrease of MMP-9 expression. Overall, FE performs a cytotoxic activity and anti-migration activity on 4T1 breast cancer cells.Keywords: Boesenbergia pandurata, cytotoxic, ROS, anti-migration, 4T1
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Ma, Qizhi, Yue Chen, Qing Qin, Fuchun Guo, Yong-sheng Wang, and Dan Li. "CXCL13 expression in mouse 4T1 breast cancer microenvironment elicits antitumor immune response by regulating immune cell infiltration." Precision Clinical Medicine 4, no. 3 (August 4, 2021): 155–67. http://dx.doi.org/10.1093/pcmedi/pbab020.
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Abstract Breast cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related deaths among women worldwide. Previous studies have reported contradictory performance of chemokine CXC motif ligand 13 (CXCL13) in breast cancer. In this study, The Cancer Genome Atlas database analysis revealed that CXCL13 was overexpressed in various human cancers including breast carcinoma, and associated with good clinical prognosis in breast cancer. Flow cytometry detection also found upregulated intracellular CXCL13 expression in human breast cancer cell lines. To explore the possible role of CXCL13 in the breast cancer microenvironment, mouse triple negative breast cancer (TNBC) was lentivirally transfected to stably overexpress mouse CXCL13 (4T1-CXCL13). Both parental 4T1 and 4T1-CXCL13 strains showed no in vitro or in vivo endogenous cell surface CXCR5 expression. In immune-competent BALB/c mice, the in vivo tumor growth of 4T1-CXCL13 was significantly inhibited and even completely eradicated, accompanied with increased infiltrations of CD4+, CD8+ T lymphocytes and CD11b+CD11c+ DCs. Further investigations showed that CXCL13 expression in the 4T1 tumor microenvironment elicited long-term antitumor immune memory, and rejection of distal parental tumor. The antitumor activity of CXCL13 was remarkedly impaired in BALB/cA-nu nude mice, or in BALB/c mice with CD8+ T lymphocyte or NK cell depletion. Our investigation indicated that CXCL13 expression in TNBC triggered effective antitumor immunity by chemoattracting immune cell infiltrations and could be considered as a novel prognostic marker for TNBC.
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Harahap, Urip, Poppy Anjelisa Zaitun Hasibuan, Panal Sitorus, and Denny Satria. "CYTOTOXICITY ACTIVITY OF PICRIA FEL-TERRAE LOUR. HERBS AGAINST 4T1 AND MCF-7 BREAST CANCER CELLS." Asian Journal of Pharmaceutical and Clinical Research 11, no. 13 (April 26, 2018): 194. http://dx.doi.org/10.22159/ajpcr.2018.v11s1.26608.
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Objective: This study was carried out to investigate the cytotoxic activity toward 4T1 and MCF-7 cell lines of Picria fel-terrae Lour. herb fractions.Methods: P. fel-terrae Lour. herb powder was extracted by maceration method with n-hexane, ethyl acetate, and ethanol solvent. In vitro study was using MTT method toward 4T1 and MCF-7 cell lines.Results: The inhibitory concentration 50% was 234.10 ± 7.85, 50.49 ± 1.07, and 212.53 ± 7.55 μg/mL for 4T1 and 84.62 ± 1.44, 56.79 ± 0.22, and 235.51 ± 4.77 μg/mL for MCF-7 cell lines, respectively.Conclusion: The results reveal that P. fel-terrae Lour. herb fractions provide effective as anticancer. Our further study is to assess the mechanism of ethyl acetate fraction in inhibit angiogenesis and metastatic in breast cancer.
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Papiernik, Diana, Anna Urbaniak, Dagmara Kłopotowska, Anna Nasulewicz-Goldeman, Marcin Ekiert, Marcin Nowak, Joanna Jarosz, et al. "Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors." Cancers 12, no. 3 (March 7, 2020): 623. http://dx.doi.org/10.3390/cancers12030623.
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Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with Rbp4 (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor.
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Dorostkar, Ruhollah, Mohammad Sadegh Hashemzadeh, Sajjad Jafari, Mahdi Tat, Majdedin Ghalavand, Mohammad Hossein Asghari, and Milad Moloudizargari. "Immunotherapeutic efficacy of a Lactobacillus casei lysate as an adjuvant combined with a heated-4T1 mammary carcinoma cell lysate in a murine model of breast cancer." Asian Biomedicine 10, no. 4 (January 31, 2017): 327–34. http://dx.doi.org/10.5372/1905-7415.1004.494.
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Abstract Background Immunotherapy, during which the immune system of the patient is manipulated to act against tumors has been among the most successful methods in the treatment of breast cancer, a leading cause of mortality among women worldwide. Objectives To investigate the immunotherapeutic efficacy of Lactobacillus casei lysate as an adjuvant in combination with a heated-4T1 mammary carcinoma cell lysate in a model of breast cancer. Methods After ethics committee approval of all animal procedures, a murine model of breast cancer was induced in BALB/c mice using 4T1 cells. These mice were immunized with a combination of lysates of heated 4T1 cells and L. casei. Subsequent changes in tumor size and weight, and the production of TNF-α, IL-2, IL-12, IL-17, and IL13 were measured. Lung weights were measured as an indicator of metastasis to other organs. Results The tumor size and weight in mice immunized with the combined vaccine were significantly reduced compared with controls. The combined immunotherapy altered the pattern of cytokine production to the advantage of antitumor immunity, and was significantly more potent than immunization with heated-4T1-cell lysate or L. casei lysate alone. Conclusions Coadministration of L. casei lysate enhanced the immunotherapeutic efficacy of the heated-4T1-cell lysate as a source of tumor-associated antigens. L. casei can potentially be used as an adjuvant combined with sources of tumor antigens in the treatment of cancers, and as a safe alternative to the current adjuvants that cause greater irritation to hosts. Further studies are required to clarify the mechanisms underlying these effects.
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Nordin, Noraini, Swee Keong Yeap, Heshu Sulaiman Rahman, Nur Rizi Zamberi, Nurul Elyani Mohamad, Nadiah Abu, Mas Jaffri Masarudin, Rasedee Abdullah, and Noorjahan Banu Alitheen. "Antitumor and Anti-Metastatic Effects of Citral-Loaded Nanostructured Lipid Carrier in 4T1-Induced Breast Cancer Mouse Model." Molecules 25, no. 11 (June 9, 2020): 2670. http://dx.doi.org/10.3390/molecules25112670.
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Cancer nano-therapy has been progressing rapidly with the introduction of many novel drug delivery systems. The previous study has reported on the in vitro cytotoxicity of citral-loaded nanostructured lipid carrier (NLC-Citral) on MDA-MB-231 cells and some preliminary in vivo antitumor effects on 4T1 breast cancer cells challenged mice. However, the in vivo apoptosis induction and anti-metastatic effects of NLC-Citral have yet to be reported. In this study, the in vitro cytotoxic, anti-migration, and anti-invasion effects of NLC-Citral were tested on 4T1 breast cancer cells. In addition, the in vivo antitumor effects of oral delivery of NLC-Citral was also evaluated on BALB/c mice induced with 4T1 cells. In vitro cytotoxicity results showed that NLC-Citral and citral gave similar IC50 values on 4T1 cells. However, wound healing, migration, and invasion assays reflected better in vitro anti-metastasis potential for NLC-Citral than citral alone. Results from the in vivo study indicated that both NLC-Citral and citral have anti-tumor and anti-metastasis effects, whereby the NLC-Citral showed better efficacy than citral in all experiments. Also, the delay of tumor progression was through the suppression of the c-myc gene expression and induction of apoptosis in the tumor. In addition, the inhibition of metastasis of 4T1 cells to lung and bone marrow by the NLC-Citral and citral treatments was correlated with the downregulation of metastasis-related genes expression including MMP-9, ICAM, iNOS, and NF-kB and the angiogenesis-related proteins including G-CSF alpha, Eotaxin, bFGF, VEGF, IL-1alpha, and M-CSF in the tumor. Moreover, NLC-Citral showed greater downregulation of MMP-9, iNOS, ICAM, Eotaxin, bFGF, VEGF, and M-CSF than citral treatment in the 4T1-challenged mice, which may contribute to the better anti-metastatic effect of the encapsulated citral. This study suggests that NLC is a potential and effective delivery system for citral to target triple-negative breast cancer.
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Kumari, Preeti, Milan Paul, Yamini Bobde, Kumbham Soniya, Sri Vishnu Kiran Rompicharla, Balaram Ghosh, and Swati Biswas. "Albumin-based lipoprotein nanoparticles for improved delivery and anticancer activity of curcumin for cancer treatment." Nanomedicine 15, no. 29 (December 2020): 2851–69. http://dx.doi.org/10.2217/nnm-2020-0232.
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Aim: To prepare curcumin (CUR)-loaded, dioleoyl phosphoethanolamine-conjugated human serum albumin nanoparticles (NPs) and to evaluate their effectiveness in breast cancer therapy. Materials & methods: The CUR-loaded NPs were physicochemically characterized and evaluated for their cytotoxicity in murine (4T1) and human breast cancer (MDA-MB-231) cell lines. The antitumor efficacy of the nanomedicine was evaluated in 4T1 tumor bearing mice. Results: The prepared NPs exhibited encapsulation and drug loading efficiencies of approximately 79 and 21%, respectively. The NPs were taken up efficiently and markedly hindered the proliferation of breast cancer cells compared with free drug. NPs exhibited greater suppression of tumor growth in 4T1 tumor bearing mice. Conclusion: CUR-human serum albumin-dioleoyl phosphoethanolamine NPs could be a potential treatment alternative for solid tumors, including breast cancer.
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Moghaddam, Farnaz D., Pejman Mortazavi, Somayeh Hamedi, Mohammad Nabiuni, and Nasim H. Roodbari. "Apoptotic Effects of Melittin on 4T1 Breast Cancer Cell Line is associated with Up Regulation of Mfn1 and Drp1 mRNA Expression." Anti-Cancer Agents in Medicinal Chemistry 20, no. 7 (July 3, 2020): 790–99. http://dx.doi.org/10.2174/1871520620666200211091451.
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Background and Purpose: Melittin, as the main ingredient of honeybee venom, that has shown anticancer properties. The present study aimed at investigating the cytotoxic impacts of melittin on 4T1 breast cancer cells. Methods: Hemolytic activity of different concentrations (0.125, 0.25, 0.5, 1, 2, 4, 8μg/ml) of melittin was assayed and then cytotoxicity of selected concentrations of melittin (2, 4, 8, 16, 32, and 64μg/ml), 2 and 4μg/ml of cisplatin and 0.513, 0.295 and 0.123μg/ml of doxorubicin was evaluated on 4T1 cells using MTT assay. We used Morphological evaluation and flow cytometric analysis was used. Real time PCR was also used to determine mRNA expression of Mfn1 and Drp1 genes. Results: All compounds showed anti-proliferative effects on the tumor cell line with different potencies. Melittin had higher cytotoxicity against 4T1 breast cancer cells (IC50= 32μg/ml-72h) and higher hemolytic activity (HD50= 1μg/ml), as compared to cisplatin and doxorubicin. Mellitin at 16 and 32μg/ml showed apoptotic effects on 4T1 cells according to the flow cytometric analysis. The Real time PCR analysis of Drp1 and Mfn1 expression in cells treated with 16μg/ml of melittin revealed an up-regulation in Drp1 and Mfn1 genes mRNA expression in comparison with control group. Treatment with 32μg/ml of melittin was also associated with a rise in mRNA expression of Drp1 and Mfn1 as compared to the control group. Conclusion: The results of this study showed that melittin has anticancer effects on 4T1 cell lines in a dose and time dependent manner and can be a good candidate for further research on breast cancer treatment.
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Shui, Yan-Mei, Gui-Yuan Lv, Le-Tian Shan, Chun-Lei Fan, Nan Tian, Li Zhang, Tong-Chuan He, and Jian-Li Gao. "Epimedin C Promotes Vascularization during BMP2-Induced Osteogenesis and Tumor-Associated Angiogenesis." American Journal of Chinese Medicine 45, no. 05 (January 2017): 1093–111. http://dx.doi.org/10.1142/s0192415x17500598.
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Epimedin C is one of the chemical markers and major flavonoids in Herba Epimedii (Yinyanghuo), which is traditionally used to treat bone diseases and gonadal dysfunction in China. Our previous study indicated that epimedin C could induce endothelial-like, but not osteogenic differentiation of C3H/10T1/2 cells in vitro. As vasculogenesis plays a pivotal role in bone formation, this study used the bone morphogenetic protein 2 (BMP2) induced ectopic bone formation model and mice 4T1 breast cancer cells co-implanted with luciferase labeled C3H/10T1/2 cells (4T1 [Formula: see text] C3H/10T1/2-Luc) model to examine the in vivo effects of Epimedin C on vasculogenesis. As a result, Epimedin C significantly increased the bone weight and blood perfusion of mice in the BMP2 induced ectopic osteogenesis model, and the bone in Epimedin C [Formula: see text] BMP2 group was more mature than that in BMP2 group. In addition, the tumor weight, blood perfusion and tumor-associated angiogenesis were also significantly increased in the Epimedin C treated 4T1 tumor bearing mice. The mRNA levels of endothelial markers, such as the platelet endothelial adhesive factor-1(CD31), the endothelial cell specific molecule-1(ESM-1), and the vascular von Willebrand factor (vWF) in mouse 4T1 mammary tumor tissue, were commonly found to occur alongside the luciferase (labeled in C3H/10T1/2 cells) expression and significantly increased after Epimedin C treatment. Taken together, Epimedin C can effectively promote vascularization both in the BMP2-depended bone formation model and in the 4T1 mammary tumor-bearing model by inducing an endothelial-like differentiation of C3H/10T1/2 in BALB/c nude mice.
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Rezakhani, Leila, Morteza Alizadeh, Esmaeel Sharifi, Mostafa Soleimannejad, and Akram Alizadeh. "Antiproliferative effects of fresh water crab hemolymph and meat extract on breast cancer cell line." Journal of Shahrekord University of Medical Sciences 23, no. 1 (March 30, 2021): 20–26. http://dx.doi.org/10.34172/jsums.2021.04.
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Background and aims: Despite the advances in drugs, side effects of chemotherapy drugs continue to exist. Therefore, more attention has been paid to the compounds derived from medicinal herbs and aquatic organisms. This study aimed to investigate the effect of freshwater crab hemolymph and meat extract on breast cancer (BC) cell line (4T1). Methods: After isolation of freshwater crab hemolymph and meat extract, protein concentration and total antioxidant capacity were analyzed by bicinchoninic acid (BCA) and cupric reducing antioxidant capacity (CUPRAC) methods. The 4T1 cells and bone marrow mesenchymal stem cells (BMSCs) were treated with crab hemolymph (1, 2, 10 mg/mL) and meat extract (0.1, 0.2 and 1 mg/mL), and cell survival was analyzed using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) at 48 and 72 hours. Nitric oxide (NO) secretion was measured by Griess method. Data were analyzed using one-way analysis of variance (ANOVA). Results: Protein concentration of 23.25 mg/mL was shown in crab hemolymph, and 2.3 mg/mL in meat extract. Total antioxidant capacity was reported as 1.036 µM/mL and 1.104 µM/mL in crab hemolymph and meat extract, respectively. Cell survival in the 4T1 cells was decreased in a dose- and time-dependent manner (P≤0.001). NO secretion of 4T1 cells was decreased after treatment with different concentrations of crab hemolymph and meat extract at 48 and 72 hours. Cellular growth was observed in BMSCs after treatment with different concentrations of crab hemolymph and meat extract at 48 and 72 hours. Conclusion: Since crab hemolymph and meat extract have protein and antioxidant activities, they can have anti-cancer effects on 4T1 cells.
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Hsieh, Chia-Chien, and Chih-Hsuan Wang. "Aspirin Disrupts the Crosstalk of Angiogenic and Inflammatory Cytokines between 4T1 Breast Cancer Cells and Macrophages." Mediators of Inflammation 2018 (June 24, 2018): 1–12. http://dx.doi.org/10.1155/2018/6380643.
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The tumor microenvironment is rich in multiple cell types that influence tumor development. Macrophages infiltrate tumors, where they are the most abundant immune cell population and secrete a number of cytokines. Aspirin acts as a chemopreventive agent against cancer development. This study investigated whether aspirin regulates crosstalk between breast cancer cells and macrophages. To study these interactions in a tumor microenvironment, a conditioned media was employed using 4T1 breast cancer cells cultured in RAW 264.7 cell-conditioned medium (RAW-CM), and a cocultured model of both cells was used. When 4T1 cells were cultured in the RAW-CM, there were increases in cell viability and secretion of the cytokines VEGF, PAI-1, TNF-α, and IL-6. Treatment with aspirin inhibited 4T1 cell growth and migration and MCP-1, PAI-1, and IL-6 production. In the coculture of both cells, aspirin inhibited secretion of MCP-1, IL-6, and TGF-β. Furthermore, aspirin significantly decreased the M2 macrophage marker CD206, but increased M1 marker CD11c expression. In summary, aspirin treatment inhibited the crosstalk of 4T1 and RAW 264.7 cells through regulation of angiogenic and inflammatory mediator production and influenced the M1/M2 macrophage subtype. This highlighted that aspirin suppresses the tumor favorable microenvironment and could be a promising agent against triple-negative breast cancer.
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Zylla, Jessica L. S., Mariah M. Hoffman, Simona Plesselova, Somshuvra Bhattacharya, Kristin Calar, Yohannes Afeworki, Pilar de la Puente, Etienne Z. Gnimpieba, W. Keith Miskimins, and Shanta M. Messerli. "Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)." Cancers 14, no. 7 (March 30, 2022): 1753. http://dx.doi.org/10.3390/cancers14071753.
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This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.
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Chung, Su, and William Montfort. "Abstract P5-10-08: Inflammation drives NOS2-Akt2 signaling in triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–10–08—P5–10–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-10-08.
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Abstract Triple negative breast cancer (TNBC) is aggressive and represents nearly 20% of all breast cancer cases. It is associated with poor prognosis due to its high metastatic capabilities and lack of targeted therapeutic treatments. To improve TNBC treatment, our goal is to better understand the molecular mechanisms that drive TNBC. Recently, inducible nitric oxide synthase (NOS2), a nitric oxide (NO) producing enzyme, has emerged as a key player in TNBC progression. High NOS2 expression in TNBC patient correlates with poor prognosis marked with increased metastasis and disease recurrence. NOS2 catalyzes L-arginine and dioxygen (O2) to produce citrulline and high, sustained levels of NO which has been shown to alter the activity of numerous signaling pathways. Depending on NO concentration and temporal and spatial levels, it has been reported to have both tumor-promoting and tumor-suppressing functions. However, the mechanism by which NOS2 drives TNBC is unclear. Akt is major oncogenic signaling pathway that regulates various aspects of tumor progression, and it has been shown that NO can activate Akt activity. The Akt family has three members, Akt1, Akt2, and Akt3, that seem to have similar and non-redundant functions in cancer. We have discovered for the first time that NOS2 specifically activates Akt2 in TNBC cells. Thus, we hypothesize that Akt2 plays a major role in NOS2 driven TNBC. Inflammatory cytokines (IFN-γ, IL-1β, and TNF-α) highly induce NOS2 in mouse 4T1 TNBC cells. We developed a real-time NO detection assay to measure NO levels in 4T1 cells and confirmed that these cells produce high levels of NO. By pharmacologically and genetically inhibiting NOS2 in the 4T1 cells, we found that NOS2 suppresses Akt2 phosphorylation but not the total levels. Furthermore, NOS2 had no effect on Akt1. The decrease in Akt2 phosphorylation was accompanied by inhibition of its downstream targets, GSK3β and FOXO3a, suggesting that NOS2 is regulating Akt2 activity. Conversely, treatment of 4T1 and human MDA-MD-231 TNBC cells with DETA/NO, a slow releasing NO donor, resulted in increased Akt2 phosphorylation with no effect on Akt1. Akt2 has been shown to promote migration, invasion, and metastasis. Using 4T1 cells, we are presently studying the function of NOS2-Akt2 signaling in TNBC. We have orthotopically injected 4T1 cells into immunocompetent mice and have found that 4T1 tumors express high levels of NOS2 as well as phosphorylated Akt2. We have knocked out NOS2 in the 4T1 cells to examine the effects of NOS2 inhibition in the mouse tumor model. Understanding the link between NOS2 and Akt2 will give further understanding on how NOS2 drives TNBC. Citation Format: Su Chung, William Montfort. Inflammation drives NOS2-Akt2 signaling in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-10-08.
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Wang, Jin-Yan, Hengyu Chen, Shu-Zhen Dai, Feng-Ying Huang, Ying-Ying Lin, Cai-Chun Wang, Lei Li, Wu-Ping Zheng, and Guang-Hong Tan. "Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity." Journal for ImmunoTherapy of Cancer 10, no. 3 (March 2022): e003950. http://dx.doi.org/10.1136/jitc-2021-003950.
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BackgroundSeveral agents for oncolytic immunotherapy have been approved for clinical use, but monotherapy is modest for most oncolytic agents. The combination of several therapeutic strategies through recombinant and nanotechnology to engineer multifunctional oncolytic viruses for oncolytic immunotherapy is a promising strategy.MethodsAn endothelium-targeting iRGD-liposome encapsulating a recombinant Newcastle disease virus (NDV), which expresses the dendritic cell (DC) chemokine MIP-3α (iNDV3α-LP), and three control liposomes were constructed. MIP-3α, HMGB1, IgG, and ATP were detected by western blotting or ELISA. The chemotaxis of DCs was examined by Transwell chambers. The phenotypes of the immune cells were analyzed by flow cytometry. The antitumor efficiency was investigated in B16 and 4T1 tumor-bearing mice. Immunofluorescence and immunohistochemistry were used to observe the localization of liposomes, molecular expression and angiogenesis. Synergistic index was calculated using the data of tumor volume, tumor angiogenesis and tumor-infiltrating lymphocytes.ResultsCompared with NDV-LP, treatment with iNDV3α-LP and NDV3α-LP induced stronger virus replication and cell lysis in B16 and 4T1 tumor cells and human umbilical vein endothelial cells (HUVECs) with the best response observed following iNDV3α-LP treatment. B16 and 4T1 cells treated with iNDV3α-LP produced more damage-associated molecular pattern molecules, including secreted HMGB1, ATP, and calreticulin. Moreover, iNDV3α-LP specifically bound to αvβ3-expressing 4T1 cells and HUVECs and to tumor neovasculature. Tumor growth was significantly suppressed, and survival was longer in iNDV3α-LP-treated B16-bearing and 4T1-bearing mice. A mechanism study showed that iNDV3α-LP treatment initiated the strongest tumor-specific cellular and humoral immune response. Moreover, iNDV3α-LP treatment could significantly suppress tumor angiogenesis and reverse the tumor immune suppressive microenvironment in both B16-bearing and 4T1-bearing mice.ConclusionsIn this study, iNDV3α-LP had several functions, such as tumor and vessel lysis, MIP-3α immunotherapy, and binding to αvβ3-expressing tumor and its neovasculature. iNDV3α-LP treatment significantly suppressed tumor angiogenesis and reversed the tumor immunosuppressive microenvironment. These findings offer a strong rationale for further clinical investigation into a combination strategy for oncolytic immunotherapy, such as the formulation iNDV3α-LP in this study.
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Brault, M. S., and R. A. Kurt. "Impact of Tumor-Derived CCL2 on Macrophage Effector Function." Journal of Biomedicine and Biotechnology 2005, no. 1 (2005): 37–43. http://dx.doi.org/10.1155/jbb.2005.37.
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Monocyte chemoattractant protein-1 (MCP-1, CCL2) is produced by many different types of cells. In the current investigation, the effect of tumor-derived CCL2 on macrophages was evaluated to determine the extent to which this chemokine influenced the innate immune response to cancer. To do this, we used the 4T1 murine mammary carcinoma cell line that constitutively expresses CCL2 and generated 4T1 expressing an antisense CCL2 transcript. The antisense-CCL2-expressing 4T1 produced no detectable CCL2. Macrophages from female BALB/c mice were exposed to supernatants from these tumor cells. The results showed that tumor-derived CCL2 was capable of modulating cytokine gene expression but not protein production in resting, activated, and tumor-associated macrophages. In addition, tumor-derived CCL2 did not affect phagocytic activity, nitric oxide production, or cytolytic activity of the macrophages. Overall, these data suggest that tumor-derived CCL2 does not directly influence macrophage-mediated antitumor activity.
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Kazłowska, Katarzyna, Hong-Ting Victor Lin, Shun-Hsien Chang, and Guo-Jane Tsai. "In VitroandIn VivoAnticancer Effects of Sterol Fraction from Red AlgaePorphyra dentata." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/493869.
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Porphyra dentata, an edible red macroalgae, is used as a folk medicine in Asia. This study evaluatedin vitroandin vivothe protective effect of a sterol fraction fromP. dentataagainst breast cancer linked to tumor-induced myeloid derived-suppressor cells (MDSCs). A sterol fraction containing cholesterol,β-sitosterol, and campesterol was prepared by solvent fractionation of methanol extract ofP. dentata in silicagel column chromatography. This sterol fractionin vitrosignificantly inhibited cell growth and induced apoptosis in 4T1 cancer cells. Intraperitoneal injection of this sterol fraction at 10 and 25 mg/kg body weight into 4T1 cell-implanted tumor BALB/c mice significantly inhibited the growth of tumor nodules and increased the survival rate of mice. This sterol fraction significantly decreased the reactive oxygen species (ROS) and arginase activity of MDSCs in tumor-bearing mice. Therefore, the sterol fraction fromP. dentatashowed potential for protecting an organism from 4T1 cell-based tumor genesis.
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Cai, L., Y. Gu, G. Srimathveeravalli, M. Maybody, H. Yarmohammadi, J. Durack, S. Solomon, H. McArthur, J. Coleman, and J. Erinjeri. "Percutaneous cryoablation in 4T1 murine breast cancer model." Journal of Vascular and Interventional Radiology 28, no. 2 (February 2017): S104. http://dx.doi.org/10.1016/j.jvir.2016.12.845.
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Souza, Cristina Maria de, Conrado de Oliveira Gamba, Cecília Bonolo de Campos, Miriam Teresa Paz Lopes, Mônica Alves Neves Diniz Ferreira, Silvia Passos Andrade, and Geovanni Dantas Cassali. "Carboplatin delays mammary cancer 4T1 growth in mice." Pathology - Research and Practice 209, no. 1 (January 2013): 24–29. http://dx.doi.org/10.1016/j.prp.2012.10.003.
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Yang, Liang, Ling Yong, Xiao Zhu, Yaoyao Feng, Yu Fu, Daming Kong, Wei Lu, and Tian-yan Zhou. "Disease progression model of 4T1 metastatic breast cancer." Journal of Pharmacokinetics and Pharmacodynamics 47, no. 1 (January 22, 2020): 105–16. http://dx.doi.org/10.1007/s10928-020-09673-5.
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Kruger, Jorg A., Charles D. Kaplan, Yunping Luo, He Zhou, Dorothy Markowitz, Rong Xiang, and Ralph A. Reisfeld. "Characterization of stem cell–like cancer cells in immune-competent mice." Blood 108, no. 12 (December 1, 2006): 3906–12. http://dx.doi.org/10.1182/blood-2006-05-024687.
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AbstractRecently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye–based side population (SP) technique to isolate and transplant stem cell–like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1highc-Kit–CD45– phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1highCD24highc-Kit–CD45–GD high2 phenotype. Reverse transcription–polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-β2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.
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Hanif, Naufa, Adam Hermawan, and Edy Meiyanto. "Caesalpinia sappan L. Ethanolic Extract Decrease Intracellular ROS Level and Senescence of 4T1 Breast Cancer Cells." Indonesian Journal of Cancer Chemoprevention 10, no. 1 (February 1, 2019): 16. http://dx.doi.org/10.14499/indonesianjcanchemoprev10iss1pp16-23.
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Highly and uncontrolled cell proliferation on cancer cells may boost ROS level intracellular accumulation up significantly. Sappan heartwood (Caesalpinia sappan L.) have been known to have cytotoxicity effect toward several cancer cells. This research was conducted to develop Caesalpinia sappan L. heartwood ethanolic extract (CSE) as chemopreventive agent which can be used as cancer therapy, looked from antioxidant and anti-senescence activity toward 4T1 breast cancer cell. CSE was obtained through maceration using ethanol 70% as solvent. Cytotoxicity activity of CSE was done by using MTT assay with IC50 as parameter. This IC50 was used as basic to the next assay, ROS assay by using DCFDA staining flowcytometry to look ROS level intracellular of CSE toward 4T1 cell and senescence assay by using senescence associated β-galactosidase (SA β-gal) assay with % cell senescence as their parameter. CSE toxic to 4T1 cell that proved from IC50 value of 25 µg/mL. Single treatment of CSE on concentration 12,5; 25; and 37.5 µg/mL able to suppress ROS level intracellular. If compared with untreated cell, single treatment of CSE on concentration 6 and 12 µg/mL showed % cell senescence not significantly different. Based on this result, CSE is cytotoxic, has antioxidant and antisenescence activity, so it has great potential to developed as chemoprevention agent on cancer therapy.Keywords : Caesalpinia sappan L., 4T1 breast cancer line, Reactive Oxygen Species (ROS), anti-senescence
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Abdel-Salam, Mostafa A. L., Bárbara Pinto, Geovanni Cassali, Lilian Bueno, Gabriela Pêgas, Fabrício Oliveira, Irismara Silva, et al. "LyeTx I-b Peptide Attenuates Tumor Burden and Metastasis in a Mouse 4T1 Breast Cancer Model." Antibiotics 10, no. 9 (September 21, 2021): 1136. http://dx.doi.org/10.3390/antibiotics10091136.
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Cationic anticancer peptides have exhibited potent anti-proliferative and anti-inflammatory effects in neoplastic illness conditions. LyeTx I-b is a synthetic peptide derived from Lycosa erythrognatha spider venom that previously showed antibiotic activity in vitro and in vivo. This study focused on the effects of LyeTxI-b on a 4T1 mouse mammary carcinoma model. Mice with a palpable tumor in the left flank were subcutaneously or intratumorally injected with LyeTx I-b (5 mg/kg), which significantly decreased the tumor volume and metastatic nodules. Histological analyses showed a large necrotic area in treated primary tumors compared to the control. LyeTxI-b reduced tumor growth and lung metastasis in the 4T1 mouse mammary carcinoma model with no signs of toxicity in healthy or cancerous mice. The mechanism of action of LyeTx I-b on the 4T1 mouse mammary carcinoma model was evaluated in vitro and is associated with induction of apoptosis and cell proliferation inhibition. Furthermore, LyeTx I-b seems to be an efficient regulator of the 4T1 tumor microenvironment by modulating several cytokines, such as TGF-β, TNF-α, IL-1β, IL-6, and IL-10, in primary tumor and lung, spleen, and brain. LyeTx I-b also plays a role in leukocytes rolling and adhesion into spinal cord microcirculation and in the number of circulating leukocytes. These data suggest a potent antineoplastic efficacy ofLyeTx I-b.
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Donati, Kim, Christelle Sépult, Natacha Rocks, Silvia Blacher, Catherine Gérard, Agnès Noel, and Didier Cataldo. "Neutrophil-Derived Interleukin 16 in Premetastatic Lungs Promotes Breast Tumor Cell Seeding." Cancer Growth and Metastasis 10 (January 1, 2017): 117906441773851. http://dx.doi.org/10.1177/1179064417738513.
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The premetastatic niche in distant organs prior to metastatic cell arrival emerged as an important step in the metastatic cascade. However, molecular mechanisms underlying this process are still poorly understood. In particular, whether neutrophil recruitment at a premetastatic stage promotes or inhibits metastatic cell seeding has to be clarified. We aimed at unraveling how neutrophil infiltration in lung parenchyma induced by the distant primary tumor influences the establishment of lung metastasis. Elevated neutrophil counts and IL-16 levels were found in premetastatic lungs in a syngenic mouse model using 4T1 tumor cells. 4T1 cell–derived soluble factors stimulated IL-16 secretion by neutrophils. The functional contribution of IL-16 is supported by metastasis burden reduction in lungs observed on instillation of an IL-16 neutralizing antibody. Moreover, IL-16 promotes in vitro 4T1 cell adhesiveness, invasiveness, and migration. In conclusion, at a premetastatic stage, neutrophil-derived IL-16 favors tumor cell engraftment in lung parenchyma.
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Susidarti, Ratna Asmah, Edy Meiyanto, Muthi' Ikawati, Normaidah Normaidah, and Nurramadhani Armada Sida. "Chemical Constituents of Indonesian Micromelum minutum Leaves and Their Cytotoxicity Against MCF-7 and 4T1 Breast Cancer Cells." Journal of Mathematical and Fundamental Sciences 53, no. 1 (June 7, 2021): 97–108. http://dx.doi.org/10.5614/j.math.fund.sci.2021.53.1.7.
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Micromelum minutum is used widely in traditional folk medicine. Although this species has been investigated extensively and several bioactive compounds have been isolated, little work has been done on Indonesian M. minutum. This research aimed to study the chemical constituents and biological activities of M. minutum cultivated in Bantimurung Bulusaraung National Park, South Sulawesi, Indonesia. The isolated compounds were assessed for their cytotoxicity towards MCF-7 and 4T1 cell lines by MTT method. The dried ground leaves of M. minutum were sequentially macerated with n-hexane, ethyl acetate, and methanol. The n-hexane and ethyl acetate extracts contained a flavonoid 5,7-dihydroxy-3,4',8-trimethoxyflavone (1) which inhibited MCF-7 and 4T1 cell viability by 50% at concentrations of 369±8 and 227±5 µM, respectively. Further separation of the ethyl acetate extract by column chromatography yielded acetyldihydromicromelin A (2) and a mixture of dihydromicromelin A (3) and dihydromicromelin B (4), which were not active toward MCF-7 and 4T1 cells.
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Susidarti, Ratna Asmah, Edy Meiyanto, Muthi Ikawati, Normaidah Normaidah, and Nurramadhani A. Sida. "Chemical Constituents of Indonesian Micromelum minutum Leaves and Their Cytotoxicity Against MCF-7 and 4T1 Breast Cancer Cells." Journal of Mathematical and Fundamental Sciences 53, no. 1 (June 7, 2021): 97–108. http://dx.doi.org/10.5614/j.fund.math.sci.2021.53.1.7.
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Micromelum minutum is used widely in traditional folk medicine. Although this species has been investigated extensively and several bioactive compounds have been isolated, little work has been done on Indonesian M. minutum. This research aimed to study the chemical constituents and biological activities of M. minutum cultivated in Bantimurung Bulusaraung National Park, South Sulawesi, Indonesia. The isolated compounds were assessed for their cytotoxicity towards MCF-7 and 4T1 cell lines by MTT method. The dried ground leaves of M. minutum were sequentially macerated with n-hexane, ethyl acetate, and methanol. The n-hexane and ethyl acetate extracts contained a flavonoid 5,7-dihydroxy-3,4',8-trimethoxyflavone (1) which inhibited MCF-7 and 4T1 cell viability by 50% at concentrations of 369±8 and 227±5 µM, respectively. Further separation of the ethyl acetate extract by column chromatography yielded acetyldihydromicromelin A (2) and a mixture of dihydromicromelin A (3) and dihydromicromelin B (4), which were not active toward MCF-7 and 4T1 cells.
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Haryanti, Sari, Yuli Widiyastuti, and Nuning Rahmawati. "Cytotoxic and MMPs inhibitory activities of Sappan Wood (Caesalpiniasappan L.): various extracts on 4T1 breast cancer cell line." Health Science Journal of Indonesia 9, no. 1 (October 11, 2018): 51–56. http://dx.doi.org/10.22435/hsji.v9i1.483.
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Latar belakang: Kayu secang (Caesalpinia sappan L.) merupakan salah satu tanaman potensial dengan berbagai khasiat obat, termasuk antikanker. Gelatinase (MMP-2 dan MMP-9) merupakan matriks metaloproteinase (MMPs) dan memiliki peran penting dalam inisiasi, invasi, dan metastasis kanker. Penelitian ini bertujuan untuk menguji aktivitas sitotoksik dan penghambatan MMP dari ekstrak kayu secang pada sel kanker payudara 4T1.
Metode: Serbuk kayu secang dibagi menjadi 4 bagian, masing-masing diekstraksi dengan pelarut berbeda. Etanol 96%, etanol 70%, dan metanol digunakan untuk metode maserasi, sedangkan air untuk metode infusa. Uji MTT digunakan untuk menentukan efek sitotoksisitas, dan uji gelatin zymography untuk mendeteksi aktivitas MMP-2 dan MMP-9. Profil fitokimia ekstrak diamati dengan Kromatografi Lapis Tipis (KLT).
Hasil: Profil fitokimia ekstrak air menunjukkan profil KLT yang berbeda, sementara tiga ekstrak lainnya memiliki profil yang sama. Ekstrak etanol 96% kayu secang memberikan efek sitotoksik paling kuat terhadap 4T1 dengan nilai IC50 13,1 μg/mL, diikuti metanol (21,4 μg/mL), etanol 70% (22,5 μg/mL) dan air (25,5 μg/mL). Analisis gelatin zymograph dengan software ImageJ menunjukkan bahwa semua ekstrak kecuali air, menghambat aktivitas gelatinolitik MMP-9
Kesimpulan: Ekstrak kayu secang dengan berbagai pelarut polar memiliki aktivitas sitotoksik dan penghambatan MMP pada sel kanker payudara 4T1 dan berpotensi untuk dikembangkan sebagai anti kanker payudara.
Kata kunci: Caesalpinia sappan, MMP, sitotoksik, 4T1
Abstract
Background: Sappan wood (Caesalpinia sappan L.) is one of potential plant with wide variety of medicinal properties, including anticancer. Gelatinases (MMP-2 and MMP-9) are the member of matrix metalloproteinases (MMPs) and having a key role in cancer initiation, invasion, and metastasis. This study evaluated the cytotoxic and MMPs inhibitory activities of sappan wood in various extract on 4T1 breast cancer cell lines.
Methods: Sappan wood powder were divided into 4 parts, each part was extracted with different solvent. Ethanol 96%, ethanol 70%, and methanol were used for maceration methods, while water for infusion method. MTT assay used to identify cytotoxicity effect, and gelatin zymography assay to detect the activity of MMP-2 and MMP-9. Phytochemical profiling of the extract were observed by Thin Layer Chromatography (TLC).
Results: Phytocemical profiling of water extract showed different TLC profile, while three others had similar profile. The results of MTT assay showed that ethanolic 96% extract exhibited the strongest cytotoxic effect against 4T1 with the IC50 value 13,1 μg/mL, followed by methanolic (21,4 μg/mL), ethanolic 70% (22,5 μg/mL) and water (25,5 μg/mL). The analysis of gelatin zymograph bands using ImageJ software proved that all extracts except water, inhibited gelatinolytic activity of MMP-9.
Conclusion: The results of the study suggest that various extract of the sappan wood have been found to posses cytotoxic and MMPs inhibitory activities.
Keywords: Caesalpinia sappan, MMP’s, cytotoxic, 4T1
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Zheng, S., W. Fu, R. Ma, Q. Huang, J. Gu, J. Zhou, K. Lu, and G. Guo. "Suppression of MD2 inhibits breast cancer in vitro and in vivo." Clinical and Translational Oncology 23, no. 9 (March 17, 2021): 1811–17. http://dx.doi.org/10.1007/s12094-021-02587-9.
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Abstract Purpose To explore the effects of the intervening measure targeting myeloid differentiation 2 (MD2) on breast cancer progression in vitro and in vivo. Methods The expression of MD2 in normal breast cells (Hs 578Bst) and three kinds of breast carcinoma cell lines (MCF-7, MDA-MB-231 s and 4T1) were detected by western blot. MTT assay was used to detect the proliferation of 4T1 cells treated by L6H21, cell migration and invasion was measured by wound healing assay and trans-well matrigel invasion assay, respectively. In addition, to further study the role of MD2 in tumor progression, we assessed the effects of inhibition of MD2 on the progression of xenograft tumors in vivo. Results The expression of MD2 is much higher in MDA-MB-231 s and 4T1cells than that in normal breast cells (Hs 578Bst) or MCF-7 cells (p < 0.05). In vitro, suppression of MD2 by L6H21 has a significant inhibition of proliferation, migration and invasion in 4T1 cells in dose-dependent manner. In vivo, L6H21 pretreatment significantly improved survival of 4T1-bearing mice (p < 0.05). Additionally, we also observed that none of the mice died from the toxic effect of 10 mg kg−1 L6H21 in 60 days. Conclusion Overall, this work indicates that suppression of MD2 shows progression inhibition in vitro and significantly prolong survival in vivo. These findings provide the potential experimental evidence for using MD2 as a therapeutic target of breast carcinoma.
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Shin, Sung-Won, Changhoon Choi, Hakyoung Kim, Yeeun Kim, Sohee Park, Shin-Yeong Kim, Ines Batinic-Haberle, and Won Park. "MnTnHex-2-PyP5+, Coupled to Radiation, Suppresses Metastasis of 4T1 and MDA-MB-231 Breast Cancer via AKT/Snail/EMT Pathways." Antioxidants 10, no. 11 (November 5, 2021): 1769. http://dx.doi.org/10.3390/antiox10111769.
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Tumor migration and invasion induced by the epithelial-to-mesenchymal transition (EMT) are prerequisites for metastasis. Here, we investigated the inhibitory effect of a mimic of superoxide dismutase (SOD), cationic Mn(III) ortho-substituted N-n-hexylpyridylporphyrin (MnTnHex-2-PyP5+, MnHex) on the metastasis of breast cancer in cellular and animal models, focusing on the migration of tumor cells and the factors that modulate this behavior. Wound healing and Transwell migration assays revealed that the migration of mouse mammary carcinoma 4T1 cells was markedly reduced during the concurrent treatment of MnHex and radiation therapy (RT) compared with that of the control and RT alone. Bioluminescence imaging showed that MnHex/RT co-treatment dramatically reduced lung metastasis of 4T1 cells in mice, compared with the sham control and both single treatments. Western blotting and immunofluorescence showed that MnHex treatment of 4T1 cells reversed the RT-induced EMT via inhibiting AKT/GSK-3β/Snail pathway in vitro, thereby decreasing cell migration and invasion. Consistently, histopathological analyses of 4T1 tumors showed that MnHex/RT reduced Snail expression, blocked EMT, and in turn suppressed metastases. Again, in the human metastatic breast cancer MDA-MB-231 cell line, MnHex inhibited metastatic potential in vitro and in vivo and suppressed the RT-induced Snail expression. In addition to our previous studies showing tumor growth inhibition, this study demonstrated that MnHex carries the ability to minimize the metastatic potential of RT-treated cancers, thus overcoming their radioresistance.
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Razak, Nursyamirah Abd, M. Nadeem Akhtar, Nadiah Abu, Wan Yong Ho, Sheau Wei Tan, Seema Zareen, Saiful Nizam bin Taj-ud-din, Kamariah Long, Noorjahan Banu Alitheen, and Swee Keong Yeap. "The in vivo anti-tumor effect of curcumin derivative (2E,6E)-2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC) on 4T1 breast cancer cells." RSC Advances 7, no. 57 (2017): 36185–92. http://dx.doi.org/10.1039/c7ra06580a.
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Ertanto, Yogi, Rohmad Yudi Utomo, Riris Istighfari Jenie, Ratna Asmah Susidarti, and Edy Meiyanto. "Anti-metastatic effect of curcumin analog pentagamaboronon-0-fructose (PGB-0-F) against 4T1 breast cancer cells." Indonesian Journal of Biotechnology 23, no. 2 (December 24, 2018): 109. http://dx.doi.org/10.22146/ijbiotech.36431.
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Development of a chemotherapeutic agent and boron carrying pharmaceutical based on triple-negative breast cancer is important due to its metastatic progression. Metastases are often more dangerous than the primary tumor and they are responsible for 90% of all cancer deaths. The purpose of this study was to explore the anti-metastatic activities of the PGB-0 complex with fructose (PGB-0-F) against 4T1 breast cancer cells. A scratch wound healing assay was carried out to determine the migration inhibition ability of PGB-0-F, while MMP-9 expression was analysed using gelatin zymography. The testing of anti-migration activity showed that PGB-0-F inhibited in 4T1 cells, whereas the gelatin zymography assay revealed a suppression of MMP-9 expression. PGB-0-F inhibited closure on 4T1 metastatic breast cancer cells line compared with the control. PGB-0-F decreased the MMP-9 expression level compared with the control. Based on these results, PGB-0-F has the potential to be developed as a chemotherapeutic agent, and especially as an anti-metastatic agent.
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Mohamad, Nurul Elyani, Nadiah Abu, Swee Keong Yeap, and Noorjahan Banu Alitheen. "Bromelain Enhances the Anti-tumor Effects of Cisplatin on 4T1 Breast Tumor Model In Vivo." Integrative Cancer Therapies 18 (January 2019): 153473541988025. http://dx.doi.org/10.1177/1534735419880258.
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Background: This study aimed to evaluate the antitumor enhancing effect of bromelain consumption on 4T1-challenged mice treated with cisplatin. Methods: Mice challenged with 4T1 triple-negative breast cancer cells received water, bromelain, cisplatin, or bromelain + cisplatin treatment for 28 days. Tumor size was measured, and lung metastasis was evaluated by clonogenic assay. Expression of tumor inflammatory genes of the harvested tumor was quantified by polymerase chain reaction array and ELISA (enzyme-linked immunosorbent assay). Results: All treatments significantly reduced the size of tumor and lung metastasis, with combination treatment showing the best effect. Also, bromelain alone and combination treatment showed downregulation of the expression of tumor inflammatory genes (Gremlin [GREM1], interleukin 1β [IL-1β], interleukin-4 [IL-4], nuclear factor κB subunit 1 [NFκB1], and prostaglandin-endoperoxide synthase 2 [PTGS2]), tumor nitric oxide level, and serum IL-1β, and IL-4 levels. On the other hand, cisplatin treatment increased the expression of selected inflammatory markers. Conclusion: This study suggests that bromelain treatment could potentiate the antitumor effect of cisplatin on triple-negative breast cancer 4T1 cells through modulating the tumor environmental inflammation.