PT  - JOURNAL ARTICLE
AU  - Viktoryia Sidarovich
AU  - Valentina Adami
AU  - Pamela Gatto
AU  - Valentina Greco
AU  - Toma Tebaldi
AU  - Gian Paolo Tonini
AU  - Alessandro Quattrone
TI  - Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells
AID  - 10.1124/mol.114.095729
DP  - 2015 Mar 01
TA  - Molecular Pharmacology
PG  - 513--524
VI  - 87
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/87/3/513.short
4100  - http://molpharm.aspetjournals.org/content/87/3/513.full
SO  - Mol Pharmacol2015 Mar 01; 87
AB  - Iron is an essential cellular nutrient, being a critical cofactor of several proteins involved in cell growth and replication. Compared with normal cells, neoplastic cells have been shown to require a greater amount of iron, thus laying the basis for the promising anticancer 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 an inhibition of growth of 50% below 10 µM; four of the six molecules—ciclopirox olamine (CPX), piroctone, 8-hydroxyquinoline, and deferasirox—were also shown to efficiently chelate intracellular iron within 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 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.