5-iodo-4-thio-2′-deoxyuridine as a sensitizer of X-ray induced cancer cell killing

Samanta Makurat , Paulina Spisz , Witold Kozak , Janusz Rak , Magdalena Zdrowowicz

Abstract

Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 µM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy.
Author Samanta Makurat (FCh / DPCh / LBS)
Samanta Makurat,,
- Laboratory of Biological Sensitizers
, Paulina Spisz (FCh / DPCh / LBS)
Paulina Spisz,,
- Laboratory of Biological Sensitizers
, Witold Kozak (FCh / DPCh / LBS)
Witold Kozak,,
- Laboratory of Biological Sensitizers
, Janusz Rak (FCh / DPCh / LBS)
Janusz Rak,,
- Laboratory of Biological Sensitizers
, Magdalena Zdrowowicz (FCh / DPCh / LBS)
Magdalena Zdrowowicz,,
- Laboratory of Biological Sensitizers
Journal seriesInternational Journal of Molecular Sciences, ISSN 1422-0067, (N/A 100 pkt)
Issue year2019
Vol20
No6
Pages1-14
Publication size in sheets0.65
Article number1308
Keywords in Englishradiosensitizer, radiotherapy, X-ray, modified nucleosides
ASJC Classification1604 Inorganic Chemistry; 1605 Organic Chemistry; 1606 Physical and Theoretical Chemistry; 1706 Computer Science Applications; 1607 Spectroscopy; 1312 Molecular Biology; 2700 General Medicine; 1503 Catalysis
DOIDOI:10.3390/ijms20061308
URL https://doi.org/10.3390/ijms20061308
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 21-11-2019, ArticleFromJournal
Publication indicators WoS Citations = 1; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.224; WoS Impact Factor: 2018 = 4.183 (2) - 2018=4.331 (5)
Citation count*2 (2019-12-08)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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