Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Lertsuwan, Jomnarong; Ruchirawat, Mathuros

doi:10.21873/anticanres.11725

Cited by 6 publications

(8 citation statements)

References 32 publications

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“…Adenosine has been found to both inhibit and stimulate the proliferation of cancer cells [26]. As in our study, an overwhelming number of publications describe its antiproliferative activity, including in prostate cancer [30], ovarian cancer [31], cholangiocarcinoma [32] and AML [28,29]. ATP and ADP (in the low micromolar range) are competitive inhibitors of 5 -nucleotidase that hydrolyze AMP to adenosine and inorganic phosphate.…”

Section: Discussionsupporting

confidence: 65%

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

Puchałowicz

Tarnowski

Tkacz

et al. 2020

IJMS

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A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone marrow milieu in response to leukemic cell growth. Therefore, our study aimed to evaluate the effects of extracellular adenine nucleotides and adenosine on the growth and death parameters in the leukemic THP-1 cell line. Cells were exposed to ATP, ADP, AMP, adenosine and nonhydrolyzable analogues of ATP and ADP (ATPγS and ADPβS) in a 1–1000 μM broad concentration range. The basal mRNA expression of the P1 and P2 receptors was evaluated by real-time PCR. Changes in the processes of cell growth and death were assessed by flow cytometry analysis of proliferation, cell cycle and apoptosis. Chemotaxis toward stromal cell-derived factor-1 (SDF-1) was performed using the modified Boyden chamber assay, and chemokine receptor type 4 (CXCR4) surface expression was quantified by flow cytometry. We indicated several antileukemic actions. High micromolar concentrations (100–1000 μM) of extracellular adenine nucleotides and adenosine inhibit the growth of cells by arresting the cell cycle and/or inducing apoptosis. ATP is characterized by the highest potency and widest range of effects, and is responsible for the cell cycle arrest and the apoptosis induction. Compared to ATP, the effect of ADP is slightly weaker. Adenosine mostly has a cytotoxic effect, with the induction of apoptosis. The last studied nucleotide, AMP, demonstrated only a weak cytotoxic effect without affecting the cell cycle. In addition, cell migration towards SDF-1 was inhibited by low micromolar concentrations (10 μM). One of the reasons for this action of ATPγS and adenosine was a reduction in CXCR4 surface expression, but this only partially explains the mechanism of antimigratory action. In summary, extracellular adenine nucleotides and adenosine inhibit THP-1 cell growth, cause death of cells and modulate the functioning of the SDF-1/CXCR4 axis. Thus, they negatively affect the processes that are responsible for the progression of AML and the difficulties in AML treatment.

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Section: Discussionsupporting

confidence: 65%

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

Puchałowicz

Tarnowski

Tkacz

et al. 2020

IJMS

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“…We further investigated the potential molecular pathways underlying this inhibition and have demonstrated that adenosine inhibited CCA cells in a receptor-independent mechanism. Some of these cell lines including HuCCA-1, RMCCA-1 and MMNK-1 were reported to not express adenosine receptor genes, [17] while other cell lines expressed some adenosine receptor genes ( Figure S1 and Table S1). Furthermore, expression of ENPP1-3 and ENTPD1-3 (CD39 family), which convert ATP to AMP [43,44], was ubiquitous.…”

Section: Discussionmentioning

confidence: 99%

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Lertsuwan

Phoaubon

Tasnawijitwong

et al. 2020

IJMS

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Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA.

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“…HIF-1α levels are significantly elevated in cholangiocarcinoma cell lines compared to normal biliary cells and HIF-1α is important for cholangiocarcinoma cell line proliferation, migration, and invasion ( Yu et al, 2020 ). ATP and adenosine have been shown to have anti-proliferative and anti-motility effects ( Lertsuwan and Ruchirawat, 2017 ) in experiments conducted using cholangiocarcinoma cell (CCA) lines. Purinergic receptor expression levels in CCA cell lines were analyzed using qPCR and P2 receptors were expressed in CCA cell lines and in immortalized cholangiocytes, but in this study, adenosine receptors were not identified.…”

Section: Bile Duct Cancermentioning

confidence: 99%

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

Faraoni

Robson

et al. 2022

Front. Physiol.

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Adenosine 5'-triphosphate (ATP), other nucleotides, and the nucleoside analogue, adenosine, all have the capacity to modulate cellular signaling pathways. The cellular processes linked to extracellular purinergic signaling are crucial in the initiation, evolution, and resolution of inflammation. Injured or dying cells in the pancreatobiliary tract secrete or release ATP, which results in sustained purinergic signaling mediated through ATP type-2 purinergic receptors (P2R). This process can result in chronic inflammation, fibrosis, and tumor development. In contrast, signaling via the extracellular nucleoside derivative adenosine via type-1 purinergic receptors (P1R) is largely anti-inflammatory, promoting healing. Failure to resolve inflammation, as in the context of primary sclerosing cholangitis or chronic pancreatitis, is a risk factor for parenchymal and end-organ scarring with the associated risk of pancreatobiliary malignancies. Emerging immunotherapeutic strategies suggest that targeting purinergic and adenosinergic signaling can impact the growth and invasive properties of cancer cells, potentiate anti-tumor immunity, and also block angiogenesis. In this review, we dissect out implications of disordered purinergic responses in scar formation, end-organ injury, and in tumor development. We conclude by addressing promising opportunities for modulation of purinergic/adenosinergic signaling in the prevention and treatment of pancreatobiliary diseases, inclusive of cancer.

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Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Abstract: ATP and adenosine had anti-proliferative and anti-motility effects in CCA cells, while there was a smaller effect on normal cholangiocytes. These data indicate the potential use of ATP and odenosine as a novel therapy for CCA.

Cited by 6 publications

References 32 publications

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

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