Screening of SIRT6 inhibitors and activators: A novel activator has an impact on breast cancer cells - 16/04/21
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Abstract |
Sirtuin 6 (SIRT6), a member of sirtuin family (SIRT1-7), regulates a variety of cellular processes involved in aging, metabolism, and cancer. Dysregulation of SIRT6 is widely observed in different breast cancer subtypes; however, the role and function of SIRT6 in cancer development remain largely unexplored. The aim of this study was to identify novel compounds targeting SIRT6 which may provide a new approach in development of anti-cancer therapy for breast cancer. Virtual screening was utilized to discover potential compounds targeting SIRT6 for in vitro screening. In addition, novel 1,4-dihydropyridine derivatives were synthetized and further subjected for the screening. The impact of the compounds on the deacetylation activity of SIRT6 was determined with HPLC method. The anti-cancer activities were screened for a panel of breast cancer cells. A set of 1,4-dihydropyridine derivatives was identified as SIRT6 inhibitors. A SIRT6 activating compound, (2,4-dihydroxy-phenyl)–2-oxoethyl 2-(3-methyl-4-oxo-2-phenyl-4H-chromen-8-yl)acetate (later called as 4H-chromen), was discovered and it provided 30–40-fold maximal activation. 4H-chromen was proposed to bind similarly to quercetin and place to previously reported SIRT6 activator sites. 4H-chromen was investigated in various breast cancer cells, and it decreased cell proliferation in all cells as well as arrested cell cycle in triple negative cells. Overall, this study describes a highly potent SIRT6 activator and new inhibitors that represent a novel tool to study the mechanism of SIRT6 function.
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Highlights |
• | A virtual screening provided several SIRT6 modulators. |
• | 4H-chromen provided 40-fold activation whereas 1,4-dihydropyridines inhibited SIRT6. |
• | 4H-chromen showed anti-cancer activities on various breast cancer cells. |
Keywords : Activator, Breast cancer, Inhibitor, Sirtuin 6, Virtual screening
Esquema
Vol 138
Artículo 111452- juin 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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