TY - JOUR T1 - Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.095729 SP - mol.114.095729 AU - Viktoryia Sidarovich AU - Valentina Adami AU - Pamela Gatto AU - Valentina Greco AU - Toma Tebaldi AU - Gian Paolo Tonini AU - Alessandro Quattrone Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/01/06/mol.114.095729.abstract N2 - Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared to normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for a promising anti-cancer activity of iron chelators. In this work we evaluated the effects of molecules with iron chelation activity on neuroblastoma (NB) cell lines. Of the 17 iron chelators tested, six reduced cell viability of two NB cell lines with IG50 below 10 μM; four of the six molecules - ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, deferasirox - were also shown to efficiently chelate intracellular iron within the minutes after addition. Effects on cell viability of one of the compounds, CPX, were indeed dependent on chelation of intracellular iron and mediated by both G0/G1 cell cycle block and induction of apoptosis. By combined transcriptome and translatome profiling we identified early translational downregulation of several members of the heat-shock protein (HSP) group as a specific effect of CPX treatment. We functionally confirmed iron-dependent depletion of HSP90 and its client proteins at pharmacologically achievable concentrations of CPX, and we extended this effect to piroctone, 8-hydroxyquinoline and deferasirox. Given the documented sensitivity of NB cells to HSP90 inhibition, we propose CPX and other iron chelators as investigational antitumor agents in NB therapy. ER -