Copper as a Target for Treatment of Neuroblastoma: Molecular and Cellular Mechanisms

Abstract

Neuroblastoma 266 Copper uptake Ctr1 (Copper transporter 1). High-affinity Cu + importer, composed of three main domains: an extracellular N-terminal tail containing multiple copper-binding methionine residues; a transmembrane segment consisting of three α-helical regions; an intracellular C-terminal domain. Three subunits assemble to form a homo-trimeric channel (9 Å pore diameter) within the plasma membrane (see [118] for a review). Ctr2 (Copper transporter 2). Copper permease, whose structure resembles that of Ctr1. Predominantly localized to endosomes and lysosomes, it seems to provide a mechanism of copper recycling from degraded cuproenzymes [119]. PrP C (Cellular Prion protein). Endogenous copper-binding glycoprotein, mainly expressed in the central nervous system. The protein structure includes an unstructured N-terminal domain and a Cterminal globular region composed of three α-helices and two short beta-strands. When Cu 2+ ions bind to the N-terminal octapeptide repeats (residues 51-90), the protein undergoes endocytosis, that providing a route for cell copper entry [58,59]. Cytosolic transport CCS. Metallo chaperone required for copper delivery to Cu,Zn Superoxide dismutases 1; upregulated in response to copper deficiency [120]. Cox17. Metallo chaperone delivering copper to Sco1 and Cox11 proteins in order to catalyse the cytochrome c oxidase copper loading [121]. Atox1. Metallo chaperone that delivers copper to ATP7A and ATP7B Cu + efflux pumps [122]. Metallothioneins. Small cysteine-rich proteins tightly binding copper ions and buffering the ion excess [123]. Copper efflux ATP7A. Cu +-transporting P-type ATPase expressed by all cell types, with the exception of liver. Structural features include eight membrane-spanning domains and six N-terminal cysteine-rich metal binding motifs (MXCXXC) [25]. Box 1. Main proteins involved in cell copper homeostasis Neuroblastoma 268

Advances in Copper Complexes as Anticancer Agents

“…Several strategies aimed at development of new anticancer therapeutics targeting the elevated tumor-specific copper level have been proposed. − Actually, control of angiogenesis, tumor growth, and metastasis could be attained by chelating the excess of copper. In an attempt to do so, small molecules with copper-binding ability that are easily synthesized and structurally manipulated have become an attractive tool. , Examples include trientine (trien), d -penicillamine ( d -pen), and tetrathiomolybdate (TM).…”