Registration Number
0223U005328,
(0119U100158)
, R & D reports
Title
Influence of the new inhibitors of reparative enzyme MGMT on the efficiency of alkylating therapy of tumors in model systems
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Завершення експериментальної роботи і підведення підсумків дослідження in silico регуляторних сайтів у структурних елементах гена MGMT людини та його ортологів. Підготовка заключного звіту.
Head
Lukash Lyubov L., Доктор біологічних наук
Registration Date
20-12-2023
Organization
Institute of Molecular Biology and Genetics of NAS of Ukraine
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Investigation of the MGMT gene level expression and Wnt signaling activation at different stages of alkylating therapy of tumors with the usage of new inhibitors in model systems in vivo and in vitro
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The aim of this work was the discovering of new non-nucleoside inhibitors of MGMT repair enzyme, studies of their possible therapeutic effect in complex alkylating chemotherapy and their modulation of MGMT expression in model systems. These new low-molecular compounds, due to their molecular structure, especially, due to low similarity with common biomolecules, may have lower toxicity level and compatible efficacy comparing to standard O6-benzylguanine (BG) inhibitor.
Both own new inhibitors cytotoxicity and their enhancing properties in N-methyl-N’nitro-N-nitrozoguanidine-induced cytotoxicity had been studied. Evolution of MGMT gene structural elements in primates also were analyzed.
Resulting these study three new inhibitors was identified. Comparison of enhancing of alkyl-induced cytotoxicity in vitro was made for these inhibitors and O6-BG; and the higher efficacy of new inhibitors have been shown. Sufficient decrease of MGMT protein expression level under the treatment by new inhibitors also has been confirmed. Using in vivo murine spontaneous tumor model (ICR aged females) we revealed significant improving of tumor growth inhibitory chemotherapy with NG. Using both in vito and in vivo models, the participation of apoptosis and authophagy mechanisms in alkyl-sensibilizing activity of new inhibirors has been shown. But there was no evidence of Wnt-signalling involvement in this process.
In silico studies revealed substantial evolutionary changes in MGMT gene structural elements, especially in MGEs. Those changes included wide spectrum of evolutionary event, from species/genes-specific sequences formation to deletional degradation; most of them were shown to have an individual evolutional history.
Product Description
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Yatsyshyna Anna P
Tetiana P. Ruban
Kolomiiets Yurii M.
Olha V. Pidpala
Olena M. Sukhorada
Veronika O. Kushniruk
Larysa L. Matsevych
Oleksandr Y. Papuha
Zarina M. Nidoieva
Oksana O. Piven
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2023-12-20
