Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells
Clemens Zwergel, Michele Aventaggiato, Sabrina Garbo, Elisabetta Di Bello, Bruno Fassari, Beatrice Noce, Carola Castiello, Chiara Lambona, Federica Barreca, Dante Rotili, Rossella Fioravanti, Thomas Schmalz, Michael Weyand, Amelie Niedermeier, Marco Tripodi, Gianni Colotti, Clemens Steegborn, Cecilia Battistelli, Marco Tafani, Sérgio Valente, Antonello Mai
Abstract
High Resolution Image Download MS PowerPoint Slide The mitochondrial SIRT3 modulates several biological pathways such as cancer, metabolism, and hypoxia-related diseases. Recently, we discovered new 1,4-dihydropyridines, compounds 2 and 3, the latter being a SIRT3-specific activator. In the present work, a novel 2 - and 3 -related small series of compounds have been developed, with 3c displaying the strongest SIRT3 binding and activation, with a K D of 29 μM and 387% of enzyme activation. Differently, 3d was the best in enhancing glutamate dehydrogenase activity and deacetylating K68- and K122-acMnSOD in triple-negative MDA-MB-231 breast cancer cells. Tested in CAL-62 thyroid cancer and MDA-MB-231 cells, 3d displayed the strongest time- and dose-dependent reduction of cell viability and clonogenicity at a single-digit micromolar level, along with cell death, in both normoxia and hypoxia conditions. Moreover, 3d downregulated not only hypoxia-induced factors, such as HIF-1α, EPAS-1, and CA-IX, but also epithelial–mesenchymal transition master regulators and extracellular matrix components such as SNAIL1, ZEB1, SLUG, COL1A2, MMP2, and MMP9, markedly hampering MDA-MB-231 cell migration.