Cytotoxic phenanthroline derivatives alter metallostasis and redox homeostasis in neuroblastoma cells

// Irina Naletova 1, 2, * , Cristina Satriano 1, 2, * , Alessandra Curci 2, 3 , Nicola Margiotta 2, 3 , Giovanni Natile 2, 3 , Giuseppe Arena 1, 2 , Diego La Mendola 2, 4 , Vincenzo Giuseppe Nicoletti 2, 5 and Enrico Rizzarelli 1, 2 1 Department of Chemical Sciences, University of Catania, Catania, Italy 2 Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB), Bari, Italy 3 Department of Chemistry, University of Bari ‘Aldo Moro’, Bari, Italy 4 Department of Pharmacy, University of Pisa, Pisa, Italy 5 Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Catania, Italy * These authors contributed equally to this work Correspondence to: Enrico Rizzarelli, email: erizzarelli@unict.it Vincenzo Giuseppe Nicoletti, email: nicovigi@unict.it Keywords: metal homeostasis; anticancer drug; ionophores; SH-SY5Y cell line; oxidative stress Received: September 17, 2018 Accepted: November 01, 2018 Published: November 20, 2018 ABSTRACT Copper homeostasis is generally investigated focusing on a single component of the metallostasis network. Here we address several of the factors controlling the metallostasis for neuroblastoma cells (SH-SY5Y) upon treatment with 2,9-dimethyl-1,10-phenanthroline-5,6-dione (phendione) and 2,9-dimethyl-1,10-phenanthroline (cuproindione). These compounds bind and transport copper inside cells, exert their cytotoxic activity through the induction of oxidative stress, causing apoptosis and alteration of the cellular redox and copper homeostasis network. The intracellular pathway ensured by copper transporters (Ctr1, ATP7A), chaperones (CCS, ATOX, COX 17, Sco1, Sco2), small molecules (GSH) and transcription factors (p53) is scrutinised.