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7-Methylguanine: a natural DNA repair inhibitor and a promising anticancer compoundстатья Тезисы
Информация о цитировании статьи получена из
Web of Science
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 16 января 2019 г.
- Авторы: Nilov D., Kirsanov K., Antoshina E., Maluchenko N., Feofanov A., Kurgina T., Zakharenko A., Khodyreva S., Gerasimova N., Studitsky V., Lavrik O., Švedas V.
- Журнал: FEBS open bio
- Том: 8
- Номер: Supplement S1
- Год издания: 2018
- Издательство: John Wiley & Sons Inc.
- Местоположение издательства: United States
- Первая страница: 271
- Последняя страница: 272
- DOI: 10.1002/2211-5463.12453
- Аннотация: 7-Methylguanine (7-MG) is a natural compound which inhibits DNA repair protein poly(ADP-ribose)polymerase 1 (PARP-1) in vitro and thus may be considered as a potential anticancer drug candidate for a combination chemotherapy. We previously demonstrated the ability of 7-MG to suppress the activity of recombinant human PARP-1 using the radiolabeled substrate NAD+ and activated DNA, and here we present in more detail analysis of its inhibitory and anti-proliferative effects. (1) The inhibitory properties of 7-MG against purified PARP-1 were confirmed by a novel fluorescent method for the real-time measurement of the enzyme activity. 7-MG was shown to be a competitive inhibitor of NAD+ binding to the catalytic fragment of PARP-1. (2) The effect on PARP-1 binding to nucleosomes was studied using spFRET microscopy. 7-MG exhibited a minimal effect on the nucleosome structure, but induced PARP-1 trapping in non-productive complexes. (3) 7-MG cytotoxicity was evaluated on human cancer cell lines HCT116 (colorectal carcinoma) and U2OS (osteosarcoma) by measuring Sub-G1 (apoptotic) population of cells with flow cytometry. At the PARP-1 inhibitory concentrations, 7-MG itself was not cytotoxic, but it was able to accelerate apoptotic cell death in combination with cisplatin (a DNA-damaging drug). (4) QSAR-modeling of the ADMET profile of 7-MG was done with ACD/Percepta. The safety of 7-MG was predicted and confirmed by preliminary in vivo tests on mice. Despite the fact that 7-MG is a weaker inhibitor than olaparib and some other PARP inhibitors, this natural compound may possess better pharmacokinetics and an adverse-effect profile compared to synthetic inhibitors and become a promising new constituent of anticancer therapy.
- Добавил в систему: Нилов Дмитрий Константинович