Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors.
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.
Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil. Electronic address: chrisf@uenf.br.
Christiane
C
Fernandes
Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil. Electronic address: adolfo@uenf.br.
Adolfo
A
Horn
Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Bruna F
BF
Lopes
Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Erika S
ES
Bull
Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Nathália F B
NFB
Azeredo
Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Milton M
MM
Kanashiro
Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Franz V
FV
Borges
Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis/SC, Brazil.
Adailton J
AJ
Bortoluzzi
Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis/SC, Brazil.
Bruno
B
Szpoganicz
Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis/SC, Brazil.
Anderson B
AB
Pires
Laboratório de Ciências Físicas, Universidade Estadual do Norte Fluminense, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Roberto W A
RWA
Franco
Laboratório de Fisiologia e Bioquímica de Microrganismos, Universidade Estadual do Norte Fluminense Darcy Ribeiro, 28013-602 Campos dos Goytacazes/RJ, Brazil.
João Carlos de A
JCA
Almeida
Laboratório de Fisiologia e Bioquímica de Microrganismos, Universidade Estadual do Norte Fluminense Darcy Ribeiro, 28013-602 Campos dos Goytacazes/RJ, Brazil.
Leide L F
LLF
Maciel
Laboratório de Difração de Raios X, Universidade Federal Fluminense, 24020-150 Niterói/RJ, Brazil.
Jackson A L C
JALC
Resende
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Gerhard
G
Schenk
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003300:Copper / Q000737:chemistry*; D045304:Cytochromes c / Q000032:analysis; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D053218:Receptors, Death Domain / Q000378:metabolism*; D020298:U937 Cells
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D009281:Naphthalenes; D053218:Receptors, Death Domain; D003300:Copper; D045304:Cytochromes c; D020169:Caspases; D002945:Cisplatin
Apoptosis; Caspases; Copper(II) complexes; Mechanism of cell death; THP-1, U937 and PBMC cells; X-ray diffraction studies