Cytotoxic phenanthroline derivatives alter metallostasis and redox homeostasis in neuroblastoma cells

Irina Naletova; Cristina Satriano; Alessandra Curci; Nicola Margiotta; Giovanni Natile; Giuseppe Arena; Diego La Mendola; Vincenzo Giuseppe Nicoletti; Enrico Rizzarelli

doi:10.18632/oncotarget.26346

Cytotoxic phenanthroline derivatives alter metallostasis and redox homeostasis in neuroblastoma cells

Oncotarget. 2018 Nov 20;9(91):36289-36316. doi: 10.18632/oncotarget.26346.

Authors

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}, Enrico Rizzarelli^{1

2}

Affiliations

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.

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.

Keywords: SH-SY5Y cell line; anticancer drug; ionophores; metal homeostasis; oxidative stress.