scholarly journals Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4683
Author(s):  
Geng-Ruei Chang ◽  
Chan-Yen Kuo ◽  
Ming-Yang Tsai ◽  
Wei-Li Lin ◽  
Tzu-Chun Lin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Nude Mice ◽  
Colorectal Adenocarcinoma ◽  
Transforming Growth Factor ◽  
Colon Adenocarcinoma ◽  
Future Research ◽  
Related Factors ◽  
Hct 116

Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1β, TNF-α, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.

scholarly journals The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice

2021 ◽  
Vol 22 (9) ◽  
pp. 4562
Author(s):  
Ching-Feng Wu ◽  
Ching-Yang Wu ◽  
Robin Y.-Y. Chiou ◽  
Wei-Cheng Yang ◽  
Chuen-Fu Lin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Nude Mice ◽  
Transforming Growth Factor ◽  
Human Lung ◽  
Transforming Growth Factor Β ◽  
Related Factors ◽  
Human Lung Adenocarcinoma

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1β, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor β (TGF-β), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma.

scholarly journals Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver

1993 ◽  
Vol 13 (1) ◽  
pp. 320-330
Author(s):  
E P Sandgren ◽  
N C Luetteke ◽  
T H Qiu ◽  
R D Palmiter ◽  
R L Brinster ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Transforming Growth Factor ◽  
Tumor Development ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Transforming Growth Factor Alpha ◽  
Multistage Carcinogenesis ◽  
Factor Alpha

To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.

scholarly journals Pharmacology Study of the Multiple Angiogenesis Inhibitor RC28-E on Anti-Fibrosis in a Chemically Induced Lung Injury Model

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 644 ◽  
Author(s):  
Xiangying Kou ◽  
Yeying Sun ◽  
Shenjun Li ◽  
Weihua Bian ◽  
Zhihao Liu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Human Skin Fibroblast ◽  
Mrna Levels ◽  
Related Factors ◽  
Smad Pathway

Background: Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminate in tissue fibrosis, inflammation, and angiogenesis simultaneously. Multiple cell angiogenesis is an essential part of the tissue damage response, which is involved in fibrosis development. RC28-E is a novel recombinant dual decoy receptor lgG1 Fc-fusion protein that can block vascular endothelial growth factor (VEGFA), platelet-derived growth factor (PDGF), and fibroblast growth factor-2 (FGF-2) simultaneously. This protein has stepped into clinical trials (NCT03777254) for the treatment of pathological neovascularization-related diseases. Here, we report on the role of RC28-E during anti-fibrosis and its potential multitarget function in regulating fibrosis. Methods: A bleomycin-induced pulmonary fibrosis C57BL/6 mouse model was established. Hematoxylin and eosin staining (HE) and Masson staining (Masson’s) were performed to evaluate the pulmonary fibrosis based on the scoring from, Ashcroft score. Fibrosis related factors and inflammatory cytokines including HYP, α-SMA, procollagen, ICAM, IL-6, IL-1, and TNF-α were also determined at the protein and mRNA levels to characterize the fibrosis. Both mRNA and protein levels of VEGF, FGF, and transforming growth factor (TGF)-β were detected by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) analysis, respectively. Pulmonary fibrosis and related cytokines were re-evaluated in vivo after 3 doses of RC28-E (5 mg/kg, 15 mg/kg, and 50 mg/kg, ip. Tiw × 9) in comparison with a mono-target antagonist treatment (VEGF or FGF blocking). RC28-E attenuated the activation of TGF-β induced fibroblasts in vitro. Expression levels of α-SMA and collagen I, as well as proliferation and migration, were determined with the human skin fibroblast cell line Detroit 551 and primary murine pulmonary fibroblast cells. The mechanism of RC28-E via the TGF-β/Smad pathway was also investigated. Results: RC28-E exhibits significant anti-fibrosis effects on Idiopathic pulmonary fibrosis (IPF) in vivo. Moreover, TGF-β induced fibroblast activation in vitro via the inhibition of the TGF-β downstream Smad pathway, thus providing potential therapeutics for clinical disease-related fibrosis-like IPF as well as chemotherapy-induced fibrosis in cancer therapy.

scholarly journals Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

2010 ◽  
Vol 207 (1) ◽  
pp. 85-100 ◽  
Author(s):  
Sara I. Cunha ◽  
Evangelia Pardali ◽  
Midory Thorikay ◽  
Charlotte Anderberg ◽  
Lukas Hawinkels ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Transforming Growth Factor ◽  
Gene Dosage ◽  
Family Members ◽  
Activin Receptor ◽  
Receptor Like Kinase

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.

scholarly journals Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a –8-kb enhancer

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4737-4745 ◽  
Author(s):  
John E. Pimanda ◽  
W.Y. Iris Chan ◽  
Ian J. Donaldson ◽  
Mark Bowen ◽  
Anthony R. Green ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Tumor Growth ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Responses ◽  
Comparative Genomic ◽  
Exon 1

AbstractAngiogenesis is critical to the growth and regeneration of tissue but is also a key component of tumor growth and chronic inflammatory disorders. Endoglin plays a key role in angiogenesis by modulating cellular responses to transforming growth factor-β (TGF-β) signaling and is upregulated in proliferating endothelial cells. To gain insights into the transcriptional hierarchies that govern endoglin expression, we used a combination of comparative genomic, biochemical, and transgenic approaches. Both the promoter and a region 8 kb upstream of exon 1 were active in transfection assays in endothelial cells. In transgenic mice, the promoter directed low-level expression to a subset of endothelial cells. By contrast, inclusion of the –8 enhancer resulted in robust endothelial activity with additional staining in developing ear mesenchyme. Subsequent molecular analysis demonstrated that both the –8 enhancer and the promoter depend on conserved Ets sites, which were bound in endothelial cells in vivo by Fli-1, Erg, and Elf-1. This study therefore establishes the transcriptional framework within which endoglin functions during angiogenesis.

scholarly journals Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver.

1993 ◽  
Vol 13 (1) ◽  
pp. 320-330 ◽  
Author(s):  
E P Sandgren ◽  
N C Luetteke ◽  
T H Qiu ◽  
R D Palmiter ◽  
R L Brinster ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Transforming Growth Factor ◽  
Tumor Development ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Transforming Growth Factor Alpha ◽  
Multistage Carcinogenesis ◽  
Factor Alpha

To characterize the effect(s) of transforming growth factor alpha (TGF alpha) during multistage carcinogenesis, we examined tumor development in pancreas and liver of transgenic mice that coexpressed TGF alpha with either viral (simian virus 40 T antigens [TAg]) or cellular (c-myc) oncogenes. In pancreas, TGF alpha itself was not oncogenic, but it nevertheless dramatically accelerated growth of tumors induced by either oncogene alone, thereby reducing the host life span up to 60%. Coexpression of TGF alpha and TAg produced an early synergistic growth response in the entire pancreas together with the more rapid appearance of preneoplastic foci. Coexpression of TGF alpha and c-myc also accelerated tumor growth in situ and produced transplantable acinar cell carcinomas whose rate of growth was TGF alpha dependent. In liver, expression of TGF alpha alone increased the incidence of hepatic cancer in aged mice. However, coexpression of TGF alpha with c-myc or TAg markedly reduced tumor latency and accelerated tumor growth. Significantly, expression of the TGF alpha and myc transgenes in hepatic tumors was induced up to 20-fold relative to expression in surrounding nonneoplastic liver, suggesting that high-level overexpression of these proteins acts as a major stimulus for tumor development. Finally, in both pancreas and liver, combined expression of TGF alpha and c-myc produced tumors with a more malignant (less differentiated) appearance than did expression of c-myc alone, consistent with an influence of TGF alpha upon the morphological character of c-myc-induced tumor progression. These findings demonstrate the importance of TGF alpha expression during multistage carcinogenesis in vivo and point to a major role for this growth factor as a potent stimulator of tumor growth.

Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes

2003 ◽  
Vol 284 (6) ◽  
pp. C1593-C1603 ◽  
Author(s):  
Anat Gafter-Gvili ◽  
Benjamin Sredni ◽  
Rivka Gal ◽  
Uzi Gafter ◽  
Yona Kalechman
Keyword(s):  
Growth Factor ◽  
Cyclosporin A ◽  
Nude Mice ◽  
Hair Growth ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Keratinocyte Differentiation ◽  
Differentiation Markers ◽  
Activated T Cells

One of the most common side effects of treatment with cyclosporin A (CsA) is hypertrichosis. This study shows that calcineurin activity is associated with hair keratinocyte differentiation in vivo, affecting nuclear factor of activated T cells (NFAT1) activity in these cells. Treatment of nude or C57BL/6 depilated normal mice with CsA inhibited the expression of keratinocyte terminal differentiation markers associated with catagen, along with the inhibition of calcineurin and NFAT1 nuclear translocation. This was associated with induction of hair growth in nude mice and retardation of spontaneous catagen induction in depilated normal mice. Furthermore, calcineurin inhibition blocked the expression of p21waf/cip1and p27kip1, which are usually induced with differentiation. This was also associated with an increase in interleukin-1α expression (nude mice), a decrease in transforming growth factor-β (nude and normal mice), and no change in keratinocyte growth factor expression in the skin. Retardation of catagen in CsA-treated mice was accompanied by significant alterations in apoptosis-related gene product expression in hair follicle keratinocytes. The ratio of the anti-apoptotic Bcl-2 to proapoptotic Bax expression increased, and expression of p53 and interleukin-1β converting enzyme activity decreased. These data provide the first evidence that calcineurin is functionally active in follicular keratinocytes and that inhibition of the calcineurin-NFAT1 pathway in these cells in vivo by CsA enhances hair growth.

In Vitro and in Vivo Comparison of Binding of 99m-Tc-Iabeled Anti-CEA MAb F33-104 with 99m-Tc-labeled Anti-CEA MAb BW431/26

1999 ◽  
Vol 38 (04) ◽  
pp. 115-119
Author(s):  
N. Oriuchi ◽  
S. Sugiyama ◽  
M. Kuroki ◽  
Y. Matsuoka ◽  
S. Tanada ◽  
...  
Keyword(s):  
Nude Mice ◽  
Binding Capacity ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Cell Binding ◽  
Vitro Binding ◽  
Labeling Method ◽  
Human Colon Adenocarcinoma

Summary Aim: The purpose of this study was to assess the potential for radioimmunodetection (RAID) of murine anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb) F33-104 labeled with technetium-99m (99m-Tc) by a reduction-mediated labeling method. Methods: The binding capacity of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA by means of in vitro procedures such as immunoradiometric assay and cell binding assay and the biodistribution of 99m-Tc-labeled anti-CEA MAb F33-104 in normal nude mice and nude mice bearing human colon adenocarcinoma LS180 tumor were investigated and compared with 99m-Tc-labeled anti-CEA MAb BW431/26. Results: The in vitro binding rate of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA in solution and attached to the cell membrane was significantly higher than 99m-Tclabeled anti-CEA MAb BW431/261 (31.4 ± 0.95% vs. 11.9 ± 0.55% at 100 ng/mL of soluble CEA, 83.5 ± 2.84% vs. 54.0 ± 2.54% at 107 of LS 180 cells). In vivo, accumulation of 99m-Tc-labeled anti-CEA MAb F33-104 was higher at 18 h postinjection than 99m-Tc-labeled anti-CEA MAb BW431/26 (20.1 ± 3.50% ID/g vs. 14.4 ± 3.30% ID/g). 99m-Tcactivity in the kidneys of nude mice bearing tumor was higher at 18 h postinjection than at 3 h (12.8 ± 2.10% ID/g vs. 8.01 ± 2.40% ID/g of 99m-Tc-labeled anti-CEA MAb F33-104, 10.7 ± 1.70% ID/g vs. 8.10 ± 1.75% ID/g of 99m-Tc-labeled anti-CEA MAb BW431/26). Conclusion: 99m-Tc-labeled anti-CEA MAb F33-104 is a potential novel agent for RAID of recurrent colorectal cancer.

Sign in / Sign up

Export Citation Format

Share Document