Monophosphorylation by deoxycytidine kinase affects apparent cellular uptake of decitabine in HCT116 colon cancer cells.
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Ueda K, Masuda A, Fukuda M, Tanaka S, Hosokawa M, Iwakawa S
Monophosphorylation by deoxycytidine kinase affects apparent cellular uptake of decitabine in HCT116 colon cancer cells.
Drug Metab Pharmacokinet. 2017 Dec;32(6):301-310. doi: 10.1016/j.dmpk.2017.10.001. Epub 2017 Oct 10.
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- 29174536 [ View in PubMed]
- Abstract
Decitabine (DAC), a nucleoside-related DNA methylation inhibitor, is taken up into cancer cells via equilibrative nucleoside transporter 1 (ENT1), and is then monophosphorylated by deoxycytidine kinase (dCK). In the present study, we examined the contribution of dCK to the uptake of DAC in HCT116 colon cancer cells. Irinotecan and etoposide inhibited the uptake of [(3)H]-uridine and [(3)H]-DAC at 10 s and 5 min, while cytarabine and gemcitabine only inhibited that of [(3)H]-DAC at 5 min. Irinotecan and etoposide inhibited [(3)H]-DAC uptake in negative control small interfering RNA (siRNA)- or dCK siRNA-transfected cells at 10 s, whereas cytarabine and gemcitabine did not. Cytarabine and gemcitabine inhibited DAC monophosphate generation by the cytosolic proteins of HCT116 cells and recombinant human dCK protein, assessed using polyethylenimine cellulose thin-layered chromatography. Simulations using simple kinetic models showed that apparent DAC uptake in dCK and ENT1 siRNA-treated cells was attributed to its conversion to monophosphates or a decrease in the cellular flux, respectively, and that the apparent uptake of DAC in dCK-knockdown and ENT1-knockdown cells was similar at longer times, but differed at a very short time. These results suggest that the apparent uptake of DAC is affected by ENT1 and dCK in HCT116 cells.
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- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Decitabine Deoxycytidine kinase Protein Humans YesSubstrateDetails - Drug Reactions
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