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

Garcia Gil, Mercedes and Tozzi, Maria Grazia and Allegrini, Simone and Folcarelli, Serena and Della Sala, Grazia and Voccoli, Vladimir and Colombaioni, Laura and Camici, Marcella (2012) Novel metabolic aspects related to adenosine deaminase inhibition in a human astrocytoma cell line. Neurochemistry International, Vol. 60 (5), p. 523-532. ISSN 0197-0186. eISSN 1872-9754. Article.

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DOI: 10.1016/j.neuint.2012.02.008

Abstract

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.

Item Type:Article
ID Code:8596
Status:Published
Refereed:Yes
Uncontrolled Keywords:Adenosine deaminase, deoxycoformycin, human astrocytoma cell line, apoptosis, mitochondrial ROS, lactate production
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
Publisher:Elsevier Science
ISSN:0197-0186
eISSN:1872-9754
Deposited On:04 Feb 2013 16:53

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