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  3. Proof-of-principle studies on a strategy to enhance nucleotide imbalance specifically in cancer cells

Proof-of-principle studies on a strategy to enhance nucleotide imbalance specifically in cancer cells

  • Cell Death Discov. 2022 Nov 24;8(1):464. doi: 10.1038/s41420-022-01254-4.
Twana Alkasalias # 1 2,  Juan Zhang # 1,  Harsha Madapura 1 3,  Basile Dalaroun 1,  Oscar Bedoya Reina 1,  Rolf Lewensohn 4 5,  Kristina Viktorsson 4,  Abbas Salihi 1 6,  Suhas Darekar # 7 8,  Sonia Laín # 9 10
Affiliations

Affiliations

  • 1 Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, Stockholm, Sweden.
  • 2 General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Kurdistan Region, Iraq.
  • 3 Science for Life Laboratory, Stockholm, Sweden.
  • 4 Department of Oncology-Pathology, BioClinicum, Karolinska Institutet, Stockholm, Sweden.
  • 5 Theme Cancer, Patient Area Head and Neck, Lung and Skin, Karolinska University Hospital, Stockholm, Sweden.
  • 6 Department of Biology, College of Science, Salahaddin University‑Erbil, Erbil, Kurdistan Region, Iraq.
  • 7 Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, Stockholm, Sweden. suhas.darekar@ki.se.
  • 8 Science for Life Laboratory, Stockholm, Sweden. suhas.darekar@ki.se.
  • 9 Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, Stockholm, Sweden. sonia.lain@ki.se.
  • 10 Science for Life Laboratory, Stockholm, Sweden. sonia.lain@ki.se.
  • # Contributed equally.
PMID: 36424385 DOI: 10.1038/s41420-022-01254-4
Abstract

Highly specific and potent inhibitors of Dihydroorotate Dehydrogenase (DHODH), an essential Enzyme of the de novo pyrimidine ribonucleotide synthesis pathway, are in clinical trials for autoimmune diseases, viral infections and Cancer. However, because DHODH inhibitors (DHODHi) are immunosuppressants they may reduce the Anticancer activity of the immune system. Therefore, there may be a need to improve the therapeutic index of DHODHi in Cancer patients. The aim of this study was to find strategies to protect activated T cells from DHODHi and to identify Cancer types hypersensitive to these inhibitors. First, we observed that like uridine supplementation, adding cytidine to the culture medium protects T cells from DHODH blockage. Next, we identified tumor types with altered expression of pyrimidine ribonucleotide synthesis Enzymes. In this regard, we detected that the expression of cytidine deaminase (CDA), which converts cytidine into uridine, is low in an important proportion of Cancer cell lines and consistently low in neuroblastoma samples and in cell lines from neuroblastoma and small cell lung carcinoma. This suggested that in the presence of a DHODHi, an excess of cytidine would be deleterious for low CDA expressing Cancer cell lines. We show that this was the case (as could be seen almost immediately after treatment) when cells were cultured with Fetal Bovine Serum but, was significantly less evident when cultures contained human serum. One interesting feature of CDA is that aside from acting intracellularly, it is also present in human plasma/serum. Altogether, experiments using recombinant CDA, human serum, pharmacologic inhibition of CDA and T cell/Cancer cell co-cultures suggest that the therapeutic index of DHODHi could be improved by selecting patients with low-CDA expressing cancers in combination with strategies to increase cytidine or the cytidine/uridine ratio in the extracellular environment. Collectively, this proof-of-principle study warrants the discovery of agents to deplete extracellular CDA.

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