Novel metabolic aspects related to adenosine deaminase inhibition in a human astrocytoma cell line

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• 作者：Mercedes Garcia-Gil^a ; Maria Grazia Tozzi^b ; Simone Allegrini^c ; Serena Folcarelli^a ; Grazia Della Sala^d ; Vladimir Voccoli^d ; Laura Colombaioni^d ; Marcella Camici^b ; ^{mcamici@biologia.unipi.it}
• 关键词：ADA ; adenosine deaminase ; ADF ; human astrocytoma cell line ; Ado ; Adenosine ; AdoK ; adenosine kinase ; AICA ; 5-amino-4-imidazolecarbexamide ; AICAR ; AICA-ribotide ; AMPK ; AMP-activated protein kinase ; dAdo ; deoxyadenosine ; dAMP ; deoxyAMP ; dATP ; deoxyATP ; dCF
• 刊名：Neurochemistry International
• 出版年：2012
• 期刊代码：120_01970186
• 类别：bio
• 出版时间：April, 2012
• 卷：60
• 期：5
• 页码：523-532
• 文件大小：807 K

摘要

Adenosine deaminase, which catalyzes the deamination of adenosine and deoxyadenosine, plays a central role in purine metabolism. Indeed, its deficiency is associated with severe immunodeficiency and abnormalities in the functioning of many organs, including nervous system. We have mimicked an adenosine deaminase-deficient situation by incubating a human astrocytoma cell line in the presence of deoxycoformycin, a strong adenosine deaminase inhibitor, and deoxyadenosine, which accumulates in vivo when the enzyme is deficient, and have monitored the effect of the combination on cell viability, mitochondrial functions, and other metabolic features. Astrocytomas are the most common neoplastic transformations occurring in glial cell types, often characterized by a poor prognosis. Our experimental approach may provide evidence both for the response to a treatment affecting purine metabolism of a tumor reported to be particularly resistant to chemotherapeutic approaches and for the understanding of the molecular basis of neurological manifestations related to errors in purine metabolism. Cells incubated in the presence of the combination, but not those incubated with deoxyadenosine or deoxycoformycin alone, underwent apoptotic death, which appears to proceed through a mitochondrial pathway, since release of cytochrome c has been observed. The inhibition of adenosine deaminase increases both mitochondrial reactive oxygen species level and mitochondrial mass. A surprising effect of the combination is the significant reduction in lactate production, suggestive of a reduced glycolytic capacity, not ascribable to alterations in NAD⁺/NADH ratio, nor to a consumption of inorganic phosphate. This is a hitherto unknown effect presenting early during the incubation with deoxyadenosine and deoxycoformycin, which precedes their effect on cell viability.