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 pronounced in cancers with upregulated guanine nucleotide synthesis, but the mechanisms are poorly understood. We investigated this toxicity by measuring the effects of guanine nucleosides on nucleotides in Jurkat cells using HPLC. We also measured proliferation and cell death with microscopy and fluorescence-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 time points. Cell death was severe with a predominance of apoptosis. Deoxyguanosine but not guanosine increased dGTP to 800% of control. Adenosine inhibited the effects of guanosine, in part by competing for uptake. In stimulated leukocytes, guanosine and deoxyguanosine altered the nucleotide pools in a way qualitatively 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 two mechanisms: ATP depletion, causing necrosis, and the accumulation of dGTP, resulting in apoptosis.
Batiuk
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Department of Medicine, Indiana University and Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana 46202, USA.
Schnizlein-Bick
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Plotkin
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Dagher
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D000225:Adenine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D003839:Deoxyadenosines / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism*; D005434:Flow Cytometry; D006147:Guanine / Q000494:pharmacology; D006151:Guanosine / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D003839:Deoxyadenosines; D003854:Deoxyribonucleotides; D006151:Guanosine; D006147:Guanine; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D003849:Deoxyguanosine; D000225:Adenine; D000241:Adenosine