Abstract

Thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK) are required for the activation of thymidine and deoxycytidine analogs used in antiviral and anticancer therapies. Many anticancer drugs cause oxidative stress, and the rise of GSSG and other reactive oxygen species may lead to alteration in gene expression, protein, nucleic acids and lipid modifications. Here, we investigated the effects of oxidative stress and nucleoside analog on the expression and activity of TK1 and dCK. Treatment with GSSG resulted in glutathionylation of dCK and dGK but not TK1 and Dm-dNK, and glutathionylation led to increased dCK activity but decreased dGK activity. Treatment with hydrogen peroxide resulted in induction of TK1, however, the TK1 activity did not correlate with TK1 protein levels, indicating that TK1 protein was inactive. The cellular expression of dCK, however, was reduced but dCK activity was not affected at concentration <= 4 mM. Treatment with TFT or 5FdU resulted in downregulation of both TK1 and dCK. However, araC and dFdC treatment led to increased dCK protein but decreased dCK activity. In contrast, both TK1 protein and activity were upregulated after araC and dFdC treatment. Doxorubicin treatment led to upregulation of the TK1 but downregulation of dCK. In conclusion TK1 and dCK expression and activity are apparently affected by oxidative stress and treatment by nucleoside analogs. These results demonstrate the pharmacokinetic importance of characterizing the expression and activity of TK1 and dCK during chemotherapy with thymidine and deoxycytidine analogs in order to optimize their efficacy.

Keywords

Deoxycytidine kinase; doxorubicin; nucleoside analogs; oxidative stress; thymidine kinase 1

Published in

Nucleosides, Nucleotides and Nucleic Acids
2020, Volume: 39, number: 10-12, pages: 1347-1358
Publisher: TAYLOR & FRANCIS INC

SLU Authors

• Sun, Ren

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Eriksson, Staffan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Wang, Liya

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Associated SLU-program

AMR: Virus


Sustainable Development Goals

Ensure healthy lives and promote well-being for all at all ages


UKÄ Subject classification

Biochemistry and Molecular Biology


Publication identifier

DOI: https://doi.org/10.1080/15257770.2020.1720234

Permanent link to this page (URI)

https://res.slu.se/id/publ/105212