The A 2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism

Mølck, Christina; Ryall, James G.; Failla, Laura M.; Coates, Janine L; Pascussi, Jean‐Marc; Heath, Joan K.; Stewart, Gregory D.; Hollande, Frédéric

doi:10.1016/j.canlet.2016.09.018

Cited by 28 publications

(16 citation statements)

References 47 publications

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“…In addition, much of the information about ADO receptor signaling has been derived using pharmacological agents which are considered to selectively activate/block certain ADO receptor subtypes. The conclusions from studies like this are potentially confounded as other studies have shown that ADO receptor ligands can also mediate ADO receptor independent effects [212]. So, validation of signaling events should be ideally confirmed at the genetic level in primary immune cells.…”

Section: Discussionmentioning

confidence: 97%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

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The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

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Section: Discussionmentioning

confidence: 97%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

Self Cite

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“…et al, 2016 ). Purinergic responses of HT-29 cells, a colonic adenocarcinoma cell line, are mediated by P2Y 2 and/or P2Y 4 R. Enhanced expression of A 2B R on colorectal cancer cells that are proliferating suggests that antagonists to A 2B R may be a promising therapeutic target for colorectal cancer ( Ma et al, 2010 ; Molck et al, 2016 ). 8-Chloro adenosine inhibited growth of colorectal cancer cell lines 80514 and HCT116 in vivo and in vitro .…”

Section: Gut Disordersmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…SIRT3 can increase the OCR, indicating increased mitochondrial oxidative phosphorylation, which also induced increases in ROS levels. 31 The Honokiol derived from the bark of magnolia trees is a natural biphenolic compound, which is also a SIRT3 activator. 32 We found that the relative ROS levels increased significantly in CCA cells treated with Honokiol ( Figure 3C).…”

Section: Sirt3 Regulates Glucose Metabolism In Cca Cells Through Thmentioning

confidence: 99%

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

Yang

Zhou

et al. 2019

Cancer Medicine

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Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1.

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The A 2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism

Cited by 28 publications

References 47 publications

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Purinergic Signalling: Therapeutic Developments

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

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