Pharmacological Advantage of SIRT2-Selective versus pan-SIRT1-3 Inhibitors
| Autor: | Jessica Jingyi Bai, Jun Young Hong, Xuan Lu, Ananya Anmangandla, Hening Lin, Irma Fernandez |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male SIRT3 Context (language use) Antineoplastic Agents Pharmacology SIRT2 01 natural sciences Biochemistry Biological pathway 03 medical and health sciences Mice Sirtuin 2 Sirtuin 1 Cell Line Tumor Sirtuin 3 Peptide bond Animals Humans Cytotoxicity Cell Proliferation biology 010405 organic chemistry Chemistry Lysine food and beverages General Medicine Xenograft Model Antitumor Assays 0104 chemical sciences Histone Deacetylase Inhibitors Ester bond 030104 developmental biology Sirtuin biology.protein Molecular Medicine Carbamates Drug Screening Assays Antitumor |
| Zdroj: | ACS chemical biology. 16(7) |
| ISSN: | 1554-8937 |
| Popis: | Because of their involvement in various biological pathways, the sirtuin enzyme family members SIRT1, SIRT2, and SIRT3 play both tumor-promoting and tumor-suppressing roles, based on the context and experimental conditions. Thus, an interesting question is whether inhibiting one of them or inhibiting all of them would be better for treating cancers. Pharmacologically, this is difficult to address, due in part to potential off-target effects of different compounds. Compounds with almost identical properties but differing in SIRT1-3 selectivity will be useful for addressing this question. Here, we have developed a pan SIRT1-3 inhibitor (NH4-6) and a SIRT2-selective inhibitor (NH4-13) with very similar chemical structures, with the only difference being the substitution of an ester bond to an amide bond. Such a minimal difference allows us to accurately compare the anticancer effect of pan SIRT1-3 inhibition and SIRT2-selective inhibition in cellular and mouse models. NH4-6 showed stronger cytotoxicity than NH4-13 in cancer cell lines. In mice, both inhibitors showed similar anticancer efficacy. However, NH4-6 is toxic to mice, which hinders the use of higher dosages. These results highlight the advantage of SIRT2-selective inhibitors as potential anticancer therapeutics. |
| Databáze: | OpenAIRE |
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