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

Guanine nucleosides aretoxic to some forms of cancer. This toxicity is pronounced in cancerswith upregulated guanine nucleotide synthesis, but the mechanisms arepoorly understood. We investigated this toxicity by measuring theeffects of guanine nucleosides on nucleotides in Jurkat cells usingHPLC. We also measured proliferation and cell death with microscopy andfluorescence-activated cell sorting. Guanosine increased GTP to 600%and reduced ATP to 40% of control. This resulted in cell death with apredominance of necrosis. Deoxyguanosine caused similar increases inGTP but at earlier time points. Cell death was severe with apredominance of apoptosis. Deoxyguanosine but not guanosineincreased dGTP to 800% of control. Adenosine inhibited the effects ofguanosine, in part by competing for uptake. In stimulated leukocytes,guanosine and deoxyguanosine altered the nucleotide pools in a wayqualitatively similar to that observed in Jurkat cells. However,proliferation was enhanced rather than impaired. In conclusion,guanosine and deoxyguanosine are toxic to Jurkat cells through twomechanisms: ATP depletion, causing necrosis, and the accumulation ofdGTP, resulting in apoptosis.