scholarly journals Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK

2019 ◽  
Vol 20 (24) ◽  
pp. 6215 ◽  
Author(s):  
Ru-Mei Chen ◽  
Yi-Shiou Chiou ◽  
Qing-Yun Chong ◽  
Han-Ming Poh ◽  
Tuan-Zea Tan ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Cell Function ◽  
Inhibitory Effect ◽  
Survival Outcome ◽  
Trefoil Factor ◽  
Functional Roles ◽  
Pharmacological Inhibition ◽  
Trefoil Factor 3 ◽  
Synergistic Inhibitory Effect

Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor—2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.

Ce-Based Nanoparticles Loaded with Cisplatin for Tumour Radiotherapy

2020 ◽  
Vol 16 (10) ◽  
pp. 1482-1494
Author(s):  
Li Sun ◽  
Chang Jiang ◽  
Wenhai Li ◽  
Zelai He ◽  
Gengming Wang ◽  
...  
Keyword(s):  
Photoelectric Effect ◽  
Inhibitory Effect ◽  
Precipitation Method ◽  
Treatment Mode ◽  
X Ray ◽  
Transmission Electron ◽  
Good Biocompatibility ◽  
Synergistic Inhibitory Effect

The combination of radiotherapy and chemotherapy is a common and useful treatment mode for tumours. But traditional methods inevitably lead to a variety of side effects. A drug delivery system (DDS), which has good biocompatibility and strong anti-tumour ability, is expected to solve this problem. Studies have shown that Ce-based nanoparticles (NPs) have good radiosensitization effect through the photoelectric effect. Hence, cisplatin-loaded LiLuF4 :Ce3+scintillation NPs (NP + Cis) were first constructed in this study, which was synthesized by the crystal precipitation method and characterized by transmission electron microscopy (TEM). Subsequently, its toxicity was verified, and the radiosensitization effect and basic radiosensitization mechanism on tumour cells and tumour-bearing mice were researched. Results showed that NP + Cis triggered massive DNA damage and effectively inhibited cell viability in vitro under the exposure of X-ray irradiation (IR). Moreover, the experiments in vivo showed that the NP + Cis had higher biosafety, which could absorb enough irradiation and produce a synergistic inhibitory effect on tumours through the releasing of Cis. NP + Cis can improve the performance of DDS in chemoradiotherapy.

Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway

2013 ◽  
Vol 91 (4) ◽  
pp. 221-229 ◽  
Author(s):  
Li Zhao ◽  
Yun-Ying Sha ◽  
Qing Zhao ◽  
Jing Yao ◽  
Bin-Bin Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Human Tumor ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Antitumor Effects ◽  
Synergistic Inhibitory Effect ◽  
Cox 2

Combination therapies may increase the antitumor effects and reduce the adverse effects for the treatment of hepatocellular carcinoma. In this study, we determined the effects of 5-fluorouracil alone or in combination with wogonin in vitro and in vivo, and we investigated the possible mechanisms. The combination of these 2 drugs led to a decrease in survival and a significant synergistic inhibitory effect on high COX-2 expression in SMMC-7721 hepatocellular carcinoma (HCC) cells. Furthermore, the results show that this combination inhibits COX-2 expression and increases sensitivity to chemotherapeutic agents partly through regulating the PI3K/Akt signaling pathway. Moreover, the combination treatment caused a significant growth inhibition of human tumor xenografts in vivo. In conclusion, wogonin may increase the cytotoxicity of some antineoplastic agents and it can be used in combination with these agents as a novel therapeutic regimen for HCC treatment.

scholarly journals Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer Through Mediation of the LIFR/STATs Axis

2021 ◽  
Vol 8 ◽  
Author(s):  
Dandan Zheng ◽  
Yu Zhu ◽  
Yili Shen ◽  
Sisi Xiao ◽  
Lehe Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blotting ◽  
Cell Function ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Leukemia Inhibitory Factor Receptor ◽  
Antitumor Effects

BackgroundColorectal cancer (CRC) is the second deadliest malignant disease in the world and the leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC.MethodsCell function tests were performed to observe the inhibitory effect of cynaropicrin on human CRC cells (RKO, HCT116, and DLD-1). Expression levels of LIFR, P-STAT3, P-STAT4, and apoptotic proteins were detected by Western blotting. Immunoprecipitation confirmed the presence of LIFR/STAT3/STAT4 complex. Cell immunofluorescence assay was used to observe the subcellular localization of STAT3 and STAT4. In vivo efficacy of cynaropicrin was evaluated by a xenotransplantation model in nude mice.ResultsCynaropicrin significantly reduced the survival ability of human CRC cells and promoted apoptosis in a dose-dependent manner. Western blotting results suggested that the antitumor effects of cynaropicrin might be mediated by inhibition of the LIFR/STATs axis. Cynaropicrin reduced the formation of STAT3/STAT4 heterodimers and blocked their entry into the nucleus. Cynaropicrin also suppressed tumor growth in the xenograft model.ConclusionThe results showed that cynaropicrin exerted a strong inhibitory effect on CRC in vitro and in vivo. Our study concluded that cynaropicrin has potential application prospects in the field of anti-CRC therapy.

Probenecid Inhibits Platelet Responses to Aggregating Agents in Vitro and Has a Synergistic Inhibitory Effect with Penicillin G

1996 ◽  
Vol 76 (02) ◽  
pp. 239-244 ◽  
Author(s):  
M A Packham ◽  
M L Rand ◽  
D W Perry ◽  
D H Ruben ◽  
R L Kinlough-Rathbone
Keyword(s):  
Platelet Activating Factor ◽  
Anion Channel ◽  
Inhibitory Effect ◽  
Penicillin G ◽  
Dependent Manner ◽  
Fura 2 ◽  
Synergistic Inhibitory Effect ◽  
Dose Dependent

SummaryProbenecid is an anion channel blocker and uricosuric agent, originally developed to slow the rate of excretion of penicillin. It is now also administered with many other drugs to reduce their required dosages. Recently, probenecid (2.5 mM) has been used to prevent leakage of fura-2 or fluo-3 when these indicators of cytosolic Ca2+ levels have been introduced into cells. However, we found that probenecid markedly inhibited the increases in cytosolic Ca2+ caused by ADP, thrombin, the thrombin receptor-activating peptide (SFLLRN, TRAP), ADP, sodium arachidonate, the thromboxane A2 (TXA2) mimetic U46619, and platelet-activating factor (PAF). This finding precluded the use of probenecid with platelets in measurements of cytosolic Ca2+ with indicators such as fura-2. We then investigated the effects of probenecid on aggregation and release of 14C-serotonin from prelabeled platelets. Responses to all the agonists were inhibited by 2.5 mM probenecid, but concentrations as low as 0.25-0.5 mM inhibited responses to agonists that act largely via TXA2 (collagen, sodium arachidonate and U46619). Collagen-induced TXA2 formation was inhibited in a dose-dependent manner. Responses of aspirin-pretreated platelets to thrombin, SFLLRN, U46619 and PAF were also inhibited by probenecid, indicating that prevention of TXA2 formation does not account for all the inhibitory effects. The combination of probenecid with penicillin G produced additive or synergistic inhibition of platelet responses; responses dependent on TXA2 were synergistically inhibited by concentrations of the drugs that are reached in vivo. The synergistic inhibitory effect of probenecid on platelet functions could further impair hemostasis if it has already been partially compromised by the administration of other drugs.

Murine Trefoil Factor 3 Does not Directly Modulate LPS-Mediated Dendritic Cell Function

2007 ◽  
Vol 66 (1) ◽  
pp. 35-42 ◽  
Author(s):  
M. Loos ◽  
A. De Creus ◽  
L. Thim ◽  
E. Remaut ◽  
P. Rottiers
Keyword(s):  
Dendritic Cell ◽  
Cell Function ◽  
Dendritic Cell Function ◽  
Trefoil Factor ◽  
Trefoil Factor 3

scholarly journals Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer through Mediation of the LIFR/STATs Axis

2020 ◽  
Author(s):  
Dandan Zheng ◽  
Yu Zhu ◽  
Youqun Xiang ◽  
Xuanxuan Dai ◽  
Wanle Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blotting ◽  
Cell Function ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Leukemia Inhibitory Factor Receptor ◽  
Antitumor Effects

Abstract Background: Colorectal cancer (CRC) is the second deadliest malignant disease in the world, with a large number of new cases being reported every year. The leukemia inhibitory factor receptor/signal transducers and activators of transcriptions (LIFR/STATs) signaling axis plays an important role in the molecular biology of CRC. The inactivation of STATs is a promising anticancer strategy. Cynaropicrin is a sesquiterpene lactone with a variety of pharmacological functions, which may be used as a potential targeted cancer drug for the prevention or treatment of human CRC. Methods: Cell function tests were performed to observe the inhibitory effect of Cynaropicrin on human CRC cells (RKO, HCT116 and DLD1). Expression levels of LIFR, P-STAT3, P-STAT4 and apoptotic proteins were detected by Western blotting. Immunoprecipitation confirmed the presence of LIFR/STAT3/STAT4 complex. Cell immunofluorescence assay was used to observe the subcellular localization of STAT3 and STAT4. In vivo efficacy of Cynaropicrin was evaluated by a xenotransplantation model in nude mice.Results: Cynaropicrin significantly reduced the survival ability of human CRC cells and promoted apoptosis in a dose-dependent manner. Western blotting results suggested that the antitumor effects of cynaropicrin might be mediated by inhibition of the LIFR/STATs axis. Cynaropicrin reduced the formation of STAT3/STAT4 heterodimers and blocked their entry into the nucleus. Cynaropicrin also suppressed tumor growth in the HCT116 xenograft model.Conclusion: The above experimental results showed that cynaropicrin exerted a strong inhibitory effect on CRC in vitro and in vivo. Our study concluded that cynaropicrin has potential application prospects in the field of anti-CRC therapy.

Demonstration and Quantitation of Pharmacological Inhibition of Pulmonary Uptake of N-lsopropyl-123l-p-lodoamphetamine by Propranolol

1989 ◽  
Vol 28 (03) ◽  
pp. 100-104 ◽  
Author(s):  
S. F. Akber
Keyword(s):  
Binding Sites ◽  
Bolus Injection ◽  
Cell Function ◽  
Lung Pathology ◽  
Lung Uptake ◽  
Pharmacological Inhibition ◽  
Sensitive Index ◽  
Pulmonary Uptake ◽  
First Pass

The first-pass pulmonary extraction values of N-lsopropyl-123l-p-lodoamphetamine (123I-IMP) in pretreated dogs decreases from 90 to 62% as the amount of propranolol increases from 0 to 20 mg. The first-pass pulmonary extraction values of 123I-IMP in dogs with a simultaneous bolus injection of propranolol decreases from 90 to 62% as the amount of propranolol increases from 0 to 10 mg. The pulmonary extraction of 123I-IMP with a simultaneous bolus injection of ketamine and 123I-IMP decreases from 90 to 64% as the ketamine dose increases from 0 to 100 mg. These results suggest that the pulmonary uptake of 123I-IMP may be at least partially mediated by receptors. They also indicate that endothelial metabolic cell function may be a useful index of early lung pathology. Furthermore, studies of the degree of lung uptake may be a sensitive index of pathologic states in which alterations of amine binding sites have occurred.

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