Guanine nucleosides and Jurkat cell death: roles of ATP depletion and accumulation of deoxyribonucleotides

Guanine nucleosides are toxic to some forms of cancer. This toxicity is pro nounced in cancers with upregulated guanine nucleotide synthesis, but the m echanisms are poorly understood. We investigated this toxicity by measuring the effects of guanine nucleosides on nucleotides in Jurkat cells using HP LC. We also measured proliferation and cell death with microscopy and fluor escence-activated cell sorting. Guanosine increased GTP to 600% and reduced ATP to 40% of control. This resulted in cell death with a predominance of necrosis. Deoxyguanosine caused similar increases in GTP but at earlier tim e points. Cell death was severe with a predominance of apoptosis. Deoxyguan osine but not guanosine increased dGTP to 800% of control. Adenosine inhibi ted the effects of guanosine, in part by competing for uptake. In stimulate d leukocytes, guanosine and deoxyguanosine altered the nucleotide pools in a way qualitatively similar to that observed in Jurkat cells. However, prol iferation was enhanced rather than impaired. In conclusion, guanosine and d eoxyguanosine are toxic to Jurkat cells through two mechanisms: ATP depleti on, causing necrosis, and the accumulation of dGTP, resulting in apoptosis.