Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition

Kutryb–Zajac, Barbara; Mateuszuk, Łukasz; Zukowska, Paulina; Jasztal, Agnieszka; Zabielska, Magdalena; Toczek, Marta; Jabłońska, Patrycja; Zakrzewska, Agnieszka; Sitek, Barbara; Rogowski, Jan; Lango, Romuald; Słomińska, Ewa M.; Chłopicki, Stefan; Smolenski, Ryszard T.

doi:10.1093/cvr/cvw203

Cited by 43 publications

(57 citation statements)

References 61 publications

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“…Tumour volume was measured every 48 hours starting from the 14th day after cancer cell implantation. Based on our previously published study, this treatment protocol maintained the activities of plasma adenosine deaminase and vascular ecto‐adenosine deaminase at level lower than 20% throughout the duration of the experiment . 4T1 cancer cell implantation and dCF treatment did not affect mouse weight (Figure ).…”

Section: Resultsmentioning

confidence: 93%

“…Samples were collected after 0, 5, 15 and 30 minutes of incubation in 37°C and directly analysed with high‐performance liquid chromatography (HPLC). Adenosine and inosine concentrations were measured by reversed‐phase HPLC as described earlier . The rate of adenosine to inosine deamination was calculated from a linear phase of the reaction and expressed as the inosine increase over the time normalized for the weight of wet tissue [μmol/min/g tissue].…”

Section: Methodsmentioning

confidence: 99%

“…After reaching confluence at 24‐well culture plates, H5V and 4T1 cell monolayers were rinsed with PBS and pretreated for 15 minutes with increasing concentrations of dCF (0, 5, 15, 50, 150 and 500 nmol/L) in 1 mL Hanks Balanced Salt Solution (HBSS). Then, 50 μmol/L adenosine was added, and samples were collected after 0, 5, 15 and 30 minutes of incubation at 37°C and analysed with HPLC as described earlier . Cell residue was dissolved in 0.5 mol/L NaOH, and protein concentration was measured with a Bradford method according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…After reaching confluence at 24‐well culture plates, H5V, 4T1, E0771 LA (less aggressive murine breast cancer cell line originally obtained from C57Bl/6J mice), E0771 MA (more aggressive murine breast cancer cell line originally obtained from C57Bl/6J mice), PM (murine peritoneal macrophages isolated as describe earlier), human breast cancer cell lines (MDA‐MB‐231, T47D and MCF‐7), HAEC (human primary aortic endothelial cells), SC (human monocyte/macrophage cell line) were rinsed with PBS and 1 mL HBSS was added to each well. Then, to measure total adenosine deaminating activity, 50 μmol/L adenosine was added and samples were collected after 0, 5, 15 and 30 minutes of incubation at 37°C and analysed with HPLC as described earlier . To measure ADA2 activity, above assay was conducted in the presence of 10 μmol/L EHNA.…”

Section: Methodsmentioning

confidence: 99%

“…The increased activity of tumour ADA could be a reflection of ADA‐rich immune cell accumulation in malignant breast tumours . As we reported previously that activated endothelial cells also exhibit strongly increased eADA activity, ADA in tumour could also derive from actively proliferating endothelial cells during tumour angiogenesis . Because of the unclear data regarding the source of ADA in tumour development, this work focuses on cellular origin of its activity.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms

Kutryb–Zajac

Koszałka

Mierzejewska

et al. 2018

J Cellular Molecular Medi

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The activity of a cell‐surface ecto‐adenosine deaminase (eADA) is markedly increased in the endothelial activation and vascular inflammation leading to decreased adenosine concentration and alterations in adenosine signalling. Depending on the specific pathway activated, extracellular purines mediate host cell response or regulate growth and cytotoxicity on tumour cells. The aim of this study was to test the effects of adenosine deaminase inhibition by 2′deoxycoformycin (dCF) on the breast cancer development. dCF treatment decreased a tumour growth and a final tumour mass in female BALB/c mice injected orthotopically with 4T1 cancer cells. dCF also counteracted cancer‐induced endothelial dysfunction in orthotopic and intravenous 4T1 mouse breast cancer models. In turn, this low dCF dose had a minor effect on immune stimulation exerted by 4T1 cell implantation. In vitro studies revealed that dCF suppressed migration and invasion of 4T1 cells via A2a and A3 adenosine receptor activation as well as 4T1 cell adhesion and transmigration through the endothelial cell layer via A2a receptor stimulation. Similar effects of dCF were observed in human breast cancer cells. Moreover, dCF improved a barrier function of endothelial cells decreasing its permeability. This study highlights beneficial effects of adenosine deaminase inhibition on breast cancer development. The inhibition of adenosine deaminase activity by dCF reduced tumour size that was closely related to the decreased aggressiveness of tumour cells by adenosine receptor‐dependent mechanisms and endothelial protection.

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Section: Resultsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Adenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms

Kutryb–Zajac

Koszałka

Mierzejewska

et al. 2018

J Cellular Molecular Medi

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Identification of Adenosine Deaminase Inhibitors by Metal‐binding Pharmacophore Screening

et al. 2020

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Adenosine deaminase (ADA) is a human mononuclear Zn 2 + metalloenzyme that converts adenosine to inosine. ADA is a validated drug target for cancer, but there has been little recent work on the development of new therapeutics against this enzyme. The lack of new advancements can be partially attributed to an absence of suitable assays for high-throughput screening (HTS) against ADA. To facilitate more rapid drug discovery efforts for this target, an in vitro assay was developed that utilizes the enzymatic conversion of a visibly emitting adenosine analogue to the corresponding fluorescent inosine analogue by ADA, which can be monitored via fluorescence intensity changes. Utilizing this assay, a library of~350 small molecules containing metal-binding pharmacophores (MBPs) was screened in an HTS format to identify new inhibitor scaffolds against ADA. This approach yielded a new metalbinding scaffold with a K i value of 26 � 1 μM.

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Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

et al. 2019

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Background Extracellular nucleotide metabolism contributes to chronic inflammation, cell differentiation, and tissue mineralization by controlling nucleotide and adenosine concentrations and hence its purinergic effects. This study investigated location-specific changes of extracellular nucleotide metabolism in aortic valves of patients with calcific aortic valve disease (CAVD). Individual ecto-enzymes and adenosine receptors involved were analyzed together with correlation with CAVD severity and risk factors. Results Nucleotide and adenosine degradation rates were adversely modified on the aortic surface of stenotic valve as compared to ventricular side, including decreased ATP removal (1.25 ± 0.35 vs. 2.24 ± 0.61 nmol/min/cm 2 ) and adenosine production (1.32 ± 0.12 vs. 2.49 ± 0.28 nmol/min/cm 2 ) as well as increased adenosine deamination (1.28 ± 0.31 vs. 0.67 ± 0.11 nmol/min/cm 2 ). The rates of nucleotide to adenosine conversions were lower, while adenosine deamination was higher on the aortic sides of stenotic vs. non-stenotic valve. There were no differences in extracellular nucleotide metabolism between aortic and ventricular sides of non-stenotic valves. Furthermore, nucleotide degradation rates, measured on aortic side in CAVD (n = 62), negatively correlated with echocardiographic and biochemical parameters of disease severity (aortic jet velocity vs. ATP hydrolysis: r = − 0.30, p < 0.05; vs. AMP hydrolysis: r = − 0.44, p < 0.001; valvular phosphate concentration vs. ATP hydrolysis: r = − 0.26, p < 0.05; vs. AMP hydrolysis: r = − 0.25, p = 0.05) while adenosine deamination showed positive correlation trend with valvular phosphate deposits (r = 0.23, p = 0.07). Nucleotide and adenosine conversion rates also correlated with CAVD risk factors, including hyperlipidemia (AMP hydrolysis vs. serum LDL cholesterol: r = − 0.28, p = 0.05; adenosine deamination vs. total cholesterol: r = 0.25, p = 0.05; LDL cholesterol: r = 0.28, p < 0.05; triglycerides: r = 0.32, p < 0.05), hypertension (adenosine deamination vs. systolic blood pressure: r = 0.28, p < 0.05) and thrombosis (ATP

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Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition

Cited by 43 publications

References 61 publications

Adenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms

Adenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms

Identification of Adenosine Deaminase Inhibitors by Metal‐binding Pharmacophore Screening

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

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