Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors

• Published in: Journal of inorganic biochemistry 2015-12, Vol.153, p.68-87
• Main Authors: Fernandes, Christiane, Horn, Adolfo, Lopes, Bruna F., Bull, Erika S., Azeredo, Nathália F.B., Kanashiro, Milton M., Borges, Franz V., Bortoluzzi, Adailton J., Szpoganicz, Bruno, Pires, Anderson B., Franco, Roberto W.A., Almeida, João Carlos de A., Maciel, Leide L.F., Resende, Jackson A.L.C., Schenk, Gerhard
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Caspases; Caspases - metabolism; Cell Cycle Checkpoints - drug effects; Cisplatin - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - toxicity; Copper - chemistry; Copper(II) complexes; Cytochromes c - analysis; DNA Fragmentation - drug effects; Female; Humans; Ligands; Male; Mechanism of cell death; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Naphthalenes - toxicity; Receptors, Death Domain - metabolism; THP-1, U937 and PBMC cells; U937 Cells; X-ray diffraction studies
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2015.09.014

The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(μ-Cl)2Cu(HL1)]Cl2·H2O (1), [(H2L2)Cu(μ-Cl)2Cu(H2L2)]Cl2·5H2O (2), [(HL3)Cu(μ-Cl)2Cu(HL3)]Cl2·4H2O (3), [(H2L4)Cu(μ-Cl)2Cu(H2L4)]Cl2·6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25μmoldm−3) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg−1 was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg−1). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9. In this paper we present the synthesis, physico-chemical properties and cytotoxicity toward two human leukemia cell lines of four new copper(II) complexes. Complex (2) showed relevant antiproliferative effect against both cell lines and the mechanism of action starts from an extrinsic pathway and is amplified by the mitochondria. [Display omitted] •New copper(II) complexes containing naphthalene rings (alpha and beta)•X-ray diffractions studies and several investigations in solution were performed.•Complex (2) is almost four times less toxic than cisplatin, based on LD50 values.•Complex (2) exhibits higher activity than cisplatin against U937.•The apoptosis signal triggered by complex (2) starts from an extrinsic pathway.