scholarly journals Synthesis, Molecular Docking Analysis, and Biological Evaluations of Saccharide-Modified Sulfonamides as Carbonic Anhydrase IX Inhibitors

2021 ◽  
Vol 22 (24) ◽  
pp. 13610
Author(s):  
Zuopeng Zhang ◽  
Huali Yang ◽  
Ye Zhong ◽  
Yueqing Wang ◽  
Jian Wang ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Selective Inhibition ◽  
Tumour Microenvironment ◽  
Inhibitory Effect ◽  
High Expression ◽  
Osteosarcoma Cell ◽  
Ca Ix ◽  
Human Osteosarcoma Cell ◽  
High Concentrations

Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

Inhibition of Platelet Function by Antiarrhythmic Drugs, Verapamil and Disopyramide

1982 ◽  
Vol 47 (02) ◽  
pp. 150-153 ◽  
Author(s):  
P Han ◽  
C Boatwright ◽  
N G Ardlie
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Antiarrhythmic Drugs ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Second Phase ◽  
Ionophore A23187 ◽  
High Concentrations ◽  
Artery Disease

SummaryVarious cardiovascular drugs such as nitrates and propranolol, used in the treatment of coronary artery disease have been shown to have an antiplatelet effect. We have studied the in vitro effects of two antiarrhythmic drugs, verapamil and disopyramide, and have shown their inhibitory effect on platelet function. Verapamil, a calcium channel blocker, inhibited the second phase of platelet aggregation induced by adenosine diphosphate (ADP) and inhibited aggregation induced by collagen. Disopyramide similarly inhibited the second phase of platelet aggregation caused by ADP and aggregation induced by collagen. Either drug in synergism with propranolol inhibited ADP or collagen-induced platelet aggregation. Disopyramide at high concentrations inhibited arachidonic add whereas verapamil was without effect. Verapamil, but not disopyramide, inhibited aggregation induced by the ionophore A23187.

scholarly journals Anti-Metastatic and Anti-Angiogenic Effects of Curcumin Analog DK1 on Human Osteosarcoma Cells In Vitro

2021 ◽  
Vol 14 (6) ◽  
pp. 532
Author(s):  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Swee Keong Yeap ◽  
Mas Jaffri Masarudin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Safety Profile ◽  
Quantitative Polymerase Chain Reaction ◽  
Tube Formation ◽  
Osteosarcoma Cell ◽  
Curcumin Analog ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Human Osteosarcoma Cell

Osteosarcoma (OS) is a life-threatening malignant bone tumor associated with poor prognosis among children. The survival rate of the patient is still arguably low even with intensive treatment provided, plus with the inherent side effects from the chemotherapy, which gives more unfavorable outcomes. Hence, the search for potent anti-osteosarcoma agent with promising safety profile is still on going. Natural occurring substance like curcumin has gained a lot of attention due to its splendid safety profile as well as it pharmacological advantages such as anti-metastasis and anti-angiogenesis. However, natural curcumin was widely known for its poor cellular uptake, which undermines all potential that it possesses. This prompted the development of synthetically synthesized curcuminoid analog, known as (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2- en-1-one (DK1). In this present study, in vitro scratch assay, transwell migration/invasion assay, HUVEC tube formation assay, and ex vivo rat aortic ring assays were performed in order to investigate the anti-metastatic and anti-angiogenic potential of DK1. For further comprehension of DK1 mechanism on human osteosarcoma cell lines, microarray gene expression analysis, quantitative polymerase chain reaction (qPCR), and proteome profiler were adopted, providing valuable forecast from the expression of important genes and proteins related to metastasis and angiogenesis. Based on the data gathered from the bioassays, DK1 was able to inhibit the metastasis and angiogenesis of human osteosarcoma cell lines by significantly reducing the cell motility, number of migrated and invaded cells as well as the tube formation and micro-vessels sprouting. Additionally, DK1 also has significantly regulated several cancer pathways involved in OS proliferation, metastasis, and angiogenesis such as PI3K/Akt and NF-κB in both U-2 OS and MG-63. Regulation of PI3K/Akt caused up-regulation of genes related to metastasis inhibition, namely, PTEN, FOXO, PLK3, and GADD45A. Meanwhile, NF-κB pathway was regulated by mitigating the expression of NF-κB activator such as IKBKB and IKBKE in MG-63, whilst up-regulating the expression of NF-κB inhibitors such as NFKBIA and NFKBIE in U-2 OS. Finally, DK1 also has successfully hindered the metastatic and angiogenic capability of OS cell lines by down-regulating the expression of pro-metastatic genes and proteins like MMP3, COL11A1, FGF1, Endoglin, uPA, and IGFBP2 in U-2 OS. Whilst for MG-63, the significantly down-regulated oncogenes were Serpin E1, AKT2, VEGF, uPA, PD-ECGF, and Endoglin. These results suggest that curcumin analog DK1 may serve as a potential new anti-osteosarcoma agent due to its anti-metastatic and anti-angiogenic attributes.

scholarly journals LncRNA SNHG15 contributes to doxorubicin resistance of osteosarcoma cells through targeting the miR-381-3p/GFRA1 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 871-883
Author(s):  
Jinshan Zhang ◽  
Dan Rao ◽  
Haibo Ma ◽  
Defeng Kong ◽  
Xiaoming Xu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Noncoding Rna ◽  
Xenograft Model ◽  
Inhibitory Effect ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells

AbstractBackgroundOsteosarcoma is a common primary malignant bone cancer. Long noncoding RNA small nucleolar RNA host gene 15 (SNHG15) has been reported to play an oncogenic role in many cancers. Nevertheless, the role of SNHG15 in the doxorubicin (DXR) resistance of osteosarcoma cells has not been fully addressed.MethodsCell Counting Kit-8 assay was conducted to measure the half-maximal inhibitory concentration value of DXR in osteosarcoma cells. Western blotting was carried out to examine the levels of autophagy-related proteins and GDNF family receptor alpha-1 (GFRA1). Quantitative reverse transcription-polymerase chain reaction was performed to determine the levels of SNHG15, miR-381-3p, and GFRA1. The proliferation of osteosarcoma cells was measured by MTT assay. The binding sites between miR-381-3p and SNHG15 or GFRA1 were predicted by Starbase bioinformatics software, and the interaction was confirmed by dual-luciferase reporter assay. Murine xenograft model was established to validate the function of SNHG15 in vivo.ResultsAutophagy inhibitor 3-methyladenine sensitized DXR-resistant osteosarcoma cell lines to DXR. SNHG15 was upregulated in DXR-resistant osteosarcoma tissues and cell lines. SNHG15 knockdown inhibited the proliferation, DXR resistance, and autophagy of osteosarcoma cells. MiR-381-3p was a direct target of SNHG15, and GFRA1 bound to miR-381-3p in osteosarcoma cells. SNHG15 contributed to DXR resistance through the miR-381-3p/GFRA1 axis in vitro. SNHG15 depletion contributed to the inhibitory effect of DXR on osteosarcoma tumor growth through the miR-381-3p/GFRA1 axis in vivo.ConclusionsSNHG15 enhanced the DXR resistance of osteosarcoma cells through elevating the autophagy via targeting the miR-381-3p/GFRA1 axis. Restoration of miR-381-3p expression might be an underlying therapeutic strategy to overcome the DXR resistance of osteosarcoma.

Granulocyte Adherence is Inhibited by Radiographic Contrast Media in Vitro

1992 ◽  
Vol 33 (4) ◽  
pp. 379-383 ◽  
Author(s):  
F. Rasmussen ◽  
S. Antonsen ◽  
J. Georgsen
Keyword(s):  
Contrast Media ◽  
Whole Blood ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Autologous Plasma ◽  
Radiographic Contrast ◽  
Radiographic Contrast Media ◽  
Meglumine Diatrizoate ◽  
High Concentrations

Different amounts of diatrizoate, ioxaglate, iohexol, iodixanol, NaCl 1000 mOsm/kg, mannitol 1098 mOsm/kg, and meglumine (meglumine concentrations corresponding to the content in the diatrizoate solutions) were added to either whole blood or a suspension of granulocytes in autologous plasma, and the adherence to nylon fibers was determined. At high concentrations all the investigated contrast media (CM) inhibited granulocyte adherence. The degree of inhibition was significantly greater when the ionic CM diatrizoate and ioxaglate were used, as compared with the nonionic media. Meglumine solutions at high concentrations also inhibited adherence but significantly less than diatrizoate solutions containing the same amount of meglumine. Diatrizoate showed the greatest inhibitory effect on granulocyte adherence, and significant inhibition could be detected even with a 1.25% solution.

scholarly journals Selective Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

1977 ◽  
Author(s):  
J. D. Geratz ◽  
R. R. Tidwell ◽  
K. M. Brinkhous ◽  
S. F. Mohammad
Keyword(s):  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
The Other ◽  
Future Studies ◽  
Bovine Plasma ◽  
Inhibitory Activities ◽  
High Concentrations ◽  
Ristocetin Cofactor ◽  
Specific Inhibitors

A series of aromatic amidino compounds were investigated for their inhibitory effect on platelet agglutination and platelet aggregation. Agglutination of fresh or fixed human platelets was produced by bovine plasma or by human plasma in combination with ristocetin, while aggregation of fresh platelets was induced by ADP, thrombin or collagen. Highly effective inhibitors were found for both types of platelet clumping, but there was no parallelism between the inhibitory activities in the two test systems.5-(5-Amidino-2-benzimidazolyl)-2-(4-hydroxybenzene)benzimidazole suppressed agglutination exclusively. Pentamidine, on the other hand, strongly blocked the aggregation reactions, but did not interfere with agglutination, even at high concentrations. Compounds which inhibited aggregation also prevented the liberation of serotonin from the platelets.This investigation has led to the identification of new specific inhibitors of platelet agglutination and aggregation which can serve an important role in future studies of the two processes. The exact mode of interaction between ami dines and platelets is still being explored.. In the case of agglutination, inhibition most likely occurred at the level of binding of ristocetin cofactor to the platelet membrane. In the case of aggregation, however, interference could have taken place at the membranes or in the cytoplasm and could have been enzymatic or non-enzymatic in nature.

Ticlopidine Selectively Inhibits Human Platelet Responses to Adenosine Diphosphate

1991 ◽  
Vol 66 (06) ◽  
pp. 694-699 ◽  
Author(s):  
Marco Cattaneo ◽  
Benjaporn Akkawat ◽  
Anna Lecchi ◽  
Claudio Cimminiello ◽  
Anna M Capitanio ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Clot Retraction ◽  
Fibrinogen Binding ◽  
Low Concentrations ◽  
Binding Inhibition ◽  
High Concentrations ◽  
Formalin Fixed

SummaryPlatelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrihogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPIIb/IIIa monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their K d were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.

scholarly journals Dual-functional Liposomes with Carbonic Anhydrase IX Antibody and BR2 Peptide Modification Effectively Improve Intracellular Delivery of Cantharidin to Treat Orthotopic Hepatocellular Carcinoma Mice

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3332 ◽  
Author(s):  
Zhang ◽  
Lin ◽  
Chan ◽  
Liu ◽  
Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carbonic Anhydrase ◽  
Therapeutic Potential ◽  
Intracellular Delivery ◽  
Carbonic Anhydrase Ix ◽  
Ca Ix ◽  
Dual Functional ◽  
Peptide Modification

Liposomal nanotechnology has a great potential to overcome the current major problems of chemotherapy. However, the lack of penetrability and targetability retards the successful delivery of liposomal carriers. Previously, we showed that BR2 peptide modification endowed cantharidin-loaded liposomes with intracellular penetration that enhanced the drug cytotoxic effects. Here, we aimed to improve the targeting delivery of drugs into cancer cells via highly expressed carbonic anhydrase IX (CA IX) receptors by modifying our previous catharidin-loaded BR2-liposomes with anti-CA IX antibody. A higher cellular uptake of dual-functional liposomes (DF-Lp) than other treatments was observed. Induction of CA IX over-expressing resulted in a higher cellular binding of DF-Lp; subsequently, blocking with excess antibodies resulted in a decreased cancer-cell association, indicating a specific targeting property of our liposomes towards CA IX expressed cells. After 3h tracking, most of the liposomes were located around the nucleus which confirmed the involvement of targeting intracellular delivery. Cantharidin loaded DF-Lp exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an orthotopic hepatocellular carcinoma model compared to other groups. Collectively, our results presented the advantage of the BR2 peptide and CA IX antibody combination to elevate the therapeutic potential of cantharidin loaded DF-liposomes.

scholarly journals Lack of Small Intestinal Dysbiosis Following Long-Term Selective Inhibition of Cyclooxygenase-2 by Rofecoxib in the Rat

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 251 ◽  
Author(s):  
Bernadette Lázár ◽  
Gábor Brenner ◽  
András Makkos ◽  
Mihály Balogh ◽  
Szilvia László ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Mucosal Damage ◽  
Inhibitory Effect ◽  
Intestinal Dysbiosis ◽  
Bowel Diseases ◽  
Direct Inhibitory Effect ◽  
Cox 2 ◽  
Small Intestinal

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.

scholarly journals Formononetin Induces Apoptosis of Human Osteosarcoma Cell Line U2OS by Regulating the Expression of Bcl-2, Bax and MiR-375 In Vitro and In Vivo

2015 ◽  
Vol 37 (3) ◽  
pp. 933-939 ◽  
Author(s):  
Wei Hu ◽  
ZengMing Xiao
Keyword(s):  
Cell Line ◽  
Cell Apoptosis ◽  
Osteosarcoma Cell Line ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma Cell Line ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell ◽  
U2os Cells

Background/Aims: Phytoestrogens are known to prevent tumor progression by inhibiting proliferation and inducing apoptosis in cancer cells. Formononetin is one of the main components of red clover plants, and is considered as a typical phytoestrogen. This study investigates formononetin induction of apoptosis of human osteosarcoma cell line U2OS by regulating Bcl-2 and Bax expression in vitro and in vivo. Methods: U2OS cells were treated with different concentrations of formononetin and the proliferation of the cells was measured using an MTT assay. Cell apoptosis was examined by flow cytometry. The levels of miR-375, Bax and Bcl-2 protein expression in treated cells were determined by Western blot and RT-PCR. The antitumor activity of formononetin was also evaluated in vivo in nude mice bearing orthotopic tumor implants. Results: High concentrations of formononetin significantly suppress the proliferation of U2OS cells and induce cell apoptosis. Moreover, compared to control group the expression of Bcl-2 and miR-375 decreases with formononetin in the U2OS cells, while Bax increases. Conclusion: Formononetin has inhibitory effects on the proliferation of U2SO cells, both in vitro and in vivo. This antitumor effect is directly correlated with formononetin concentration.

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