Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5781
• Main Authors: Zakharenko, Alexandra L, Luzina, Olga A, Chepanova, Arina A, Dyrkheeva, Nadezhda S, Salakhutdinov, Nariman F, Lavrik, Olga I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-03-2023; MDPI
• Subjects: Adducts; Amino acids; Aminoglycosides; anticancer therapy; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Ataxia; Biological activity; Biological Products - pharmacology; Cancer; Cancer therapies; Care and treatment; Chemical damage; Chemical weapons; Chemotherapy; Cytotoxicity; derivative; DNA; DNA adducts; DNA damage; DNA Repair; DNA Repair Enzymes - genetics; DNA Topoisomerases, Type I - metabolism; Drugs; Enzymes; Inhibitors; Irinotecan; Kinases; Mutation; natural compound; Natural products; Organisms; Peptides; Phosphodiesterase; Phosphoric Diester Hydrolases - metabolism; Polyphenols; Review; TDP1 inhibitors; TOP1 inhibitors; Topotecan; Tumor cells; anticancer therapy; TDP1 inhibitors; derivative; TOP1 inhibitors; natural compound
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065781

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3' end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented.