Author:

Keywords:

Antineoplastic Agents, Arabinonucleosides, DNA, Neoplasm, Drug Resistance, Neoplasm, Humans, T-Lymphocytes, Tumor Cells, Cultured, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, nucleoside analogs, nucleoside kinases, 9-beta-D-arabinofuranosylguanine, chemotherapy resistance, mitochondrial DNA synthesis, HUMAN DEOXYCYTIDINE KINASE, MITOCHONDRIAL-DNA, NUCLEOSIDE TRANSPORTER, TOXICITY, DEOXYGUANOSINE, METABOLISM, 1-BETA-D-ARABINOFURANOSYLCYTOSINE, ARABINONUCLEOSIDE, 2'-DEOXYGUANOSINE, PHOSPHORYLATION, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3404 Medicinal and biomolecular chemistry

Abstract:

The guanine nucleoside analog araG is selectively toxic to T-lymphoblasts and has recently shown promise in treatment of lymphoid malignancies of T-cell origin. The molecular mechanism of this tissue-selective cytotoxicity is, however, yet unclear. AraG is phosphorylated, and thereby pharmacologically activated, by the mitochondrial deoxguanosine kinase and the cytosolic/nuclear deoxycytidine kinase. We have recently shown that araG is predominantly incorporated into mitochondrial DNA of cancer cell lines, which suggests a role of mitochondria as its pharmacological target. In the present study, we have generated araG-resistant CEM T-lymphoblast cell lines and show that araG resistance may occur by two separate molecular mechanisms that can occur sequentially. The first mechanism is associated with a decrease of araG incorporation into mitochondrial DNA, and the second event is associated with loss of dCK activity.