Mechanism of selective anticancer activity of isothiocyanates relies on differences in DNA damage repair between cancer and healthy cells

Aleksandra Hać , Joanna Brokowska , Estera Rintz , Michał Bartkowski , Grzegorz Węgrzyn , Anna Herman-Antosiewicz

Abstract

Purpose Isothiocyanates (ITCs) are compounds derived from Brassica plants with documented anticancer activity. Molecular mechanisms of their selective activity against cancer cells are still underexplored. In this work, the impact of ITC on DNA replication and damage was compared between PC-3 prostate cancer cells and HDFa normal fibroblasts as well as PNT2 prostate epithelial cells. Methods Cells were treated with sulforaphane or phenethyl isothiocyanate. [ 3H]thymidine incorporation and the level of histone γH2A.X were estimated as indicators of DNA replication and double-strand breaks (DSB), respectively. Levels of HDAC3, CtIP, and p-RPA were investigated by immunoblotting. Comet assay was performed to visualize DNA damage. Results ITCs inhibited DNA replication in all tested cell lines, and this activity was independent of reactive oxygen species of mitochondrial origin. It was followed by DSB which were more pronounced in cancer than noncancerous cells. This difference was independent of HDAC activity which was decreased in both cell lines when treated with ITCs. On the other hand, it correlated with faster removal of DSB, and thus, transient activation of repair proteins in normal cells, while in PC-3 prostate cancer, cell DNA repair was significantly less effective. Conclusion DNA damage induced by ITCs is a consequence of the block in DNA replication which is observed in both, cancer and normal cells. Selective antiproliferative activity of ITCs towards cancer cells results from less efficient DNA repair in cancer cells relative to normal cells.
Publication typeIn press (online first, early view)
Author Aleksandra Hać (FB / DMBG)
Aleksandra Hać,,
- Katedra Biologii i Genetyki Medycznej
, Joanna Brokowska (FB / DMoB)
Joanna Brokowska,,
- Department of Molecular Biology
, Estera Rintz (FB)
Estera Rintz,,
- Faculty of Biology
, Michał Bartkowski (FB)
Michał Bartkowski,,
- Faculty of Biology
, Grzegorz Węgrzyn (FB / DMoB)
Grzegorz Węgrzyn,,
- Department of Molecular Biology
, Anna Herman-Antosiewicz (FB / DMBG)
Anna Herman-Antosiewicz,,
- Katedra Biologii i Genetyki Medycznej
Journal seriesEuropean Journal of Nutrition, ISSN 1436-6207, (A 30 pkt)
Issue year2019
Noonline first
Pages1-12
Publication size in sheets0.55
Keywords in EnglishDNA replication, genotoxic stress, phenethyl isothiocyanate, sulforaphane, prostate cancer
ASJC Classification2916 Nutrition and Dietetics; 2701 Medicine (miscellaneous)
DOIDOI:10.1007/s00394-019-01995-6
URL https://doi.org/10.1007/s00394-019-01995-6
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)30
ScoreMinisterial score = 30.0, 24-07-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.153; WoS Impact Factor: 2017 = 4.423 (2) - 2017=4.125 (5)
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