2′‐Deoxyadenosine causes apoptotic cell death in a human colon carcinoma cell line

Camici²,

Allegrini³

et al. 2018

IJMS

Self Cite

The growing evidence of the involvement of purine compounds in signaling, of nucleotide imbalance in tumorigenesis, the discovery of purinosome and its regulation, cast new light on purine metabolism, indicating that well known biochemical pathways may still surprise. Adenosine deaminase is important not only to preserve functionality of immune system but also to ensure a correct development and function of central nervous system, probably because its activity regulates the extracellular concentration of adenosine and therefore its function in brain. A lot of work has been done on extracellular 5′-nucleotidase and its involvement in the purinergic signaling, but also intracellular nucleotidases, which regulate the purine nucleotide homeostasis, play unexpected roles, not only in tumorigenesis but also in brain function. Hypoxanthine guanine phosphoribosyl transferase (HPRT) appears to have a role in the purinosome formation and, therefore, in the regulation of purine synthesis rate during cell cycle with implications in brain development and tumors. The final product of purine catabolism, uric acid, also plays a recently highlighted novel role. In this review, we discuss the molecular mechanisms underlying the pathological manifestations of purine dysmetabolisms, focusing on the newly described/hypothesized roles of cytosolic 5′-nucleotidase II, adenosine kinase, adenosine deaminase, HPRT, and xanthine oxidase.

Section: Adenosine Kinase (Adk) and Adenosine Deaminase (Ada)mentioning

confidence: 99%

Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors

Camici²,

Allegrini³

et al. 2018

IJMS

Self Cite

“…In this regard, it has been demonstrated that two human colon carcinoma cell lines (LoVo and HT29) are both sensitive to this drug combination and that the extent of toxicity depends upon the level of enzymes involved both in the process of activation (phosphorylation of dAdo) and inactivation (dephosphorylation of dAMP) of dAdo [ 59 , 60 ]. The combination of dAdo and dCF in LoVo cells causes a block of the cell cycle at the S phase, and cells undergo apoptosis through a pathway involving a dATP-dependent caspase-3 activation [ 61 ]. Apoptotic cell death by dAdo and/or Ado has been also reported in sympathetic neurons and adrenal chromaffin cells [ 62 , 63 ], both deriving from the neural crest and sharing several features regarding synthesis, storage, and release of neurohormones [ 64 ].…”

Section: Regulatory Mechanisms Mediated By Dadomentioning

confidence: 99%

The Inside Story of Adenosine

Camici¹,

Tozzi³

2018

IJMS

Self Cite

Several physiological functions of adenosine (Ado) appear to be mediated by four G protein-coupled Ado receptors. Ado is produced extracellularly from the catabolism of the excreted ATP, or intracellularly from AMP, and then released through its transporter. High level of intracellular Ado occurs only at low energy charge, as an intermediate of ATP breakdown, leading to hypoxanthine production. AMP, the direct precursor of Ado, is now considered as an important stress signal inside cell triggering metabolic regulation through activation of a specific AMP-dependent protein kinase. Intracellular Ado produced from AMP by allosterically regulated nucleotidases can be regarded as a stress signal as well. To study the receptor-independent effects of Ado, several experimental approaches have been proposed, such as inhibition or silencing of key enzymes of Ado metabolism, knockdown of Ado receptors in animals, the use of antagonists, or cell treatment with deoxyadenosine, which is substrate of the enzymes acting on Ado, but is unable to interact with Ado receptors. In this way, it was demonstrated that, among other functions, intracellular Ado modulates angiogenesis by regulating promoter methylation, induces hypothermia, promotes apoptosis in sympathetic neurons, and, in the case of oxygen and glucose deprivation, exerts a cytoprotective effect by replenishing the ATP pool.

“…The combination of dAdo and dCF was found to be toxic for several tumoural cell lines such as rat hepatoma cells [64], and human colon carcinoma cell lines LoVo and HT29 [65,66,67]. The treatment with dAdo and dCF in combination resulted in the activation of the apoptotic mitochondrial pathway in LoVo, human astrocytoma, and neuroblastoma cell lines [67,68,69,70] with cytochrome c release and caspase-3 activation. Activation of caspase-8, and of both caspase-9 and -8 has also been found in astrocytoma and in neuroblastoma cells, respectively [69,70].…”

Section: Adenosine Deaminasementioning

confidence: 99%

Purine-Metabolising Enzymes and Apoptosis in Cancer

Camici¹,

Pesi³

et al. 2019

Cancers

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.