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

Fernandes, Christiane, Horn Jr, Adolfo, Lopes, Bruna F., Bull, Erika S., Azeredo, Nathália F., Kanashiro, Milton M., Borges, Franz V., Bortoluzzi, Adailton J., Szpoganicz, Bruno, Pires, Anderson B., Franco, Roberto W. A., de A. Almeida, João Carlos, Maciel, Leide L. F., Resende, Jackson A. L. C. and Schenk, Gerhard (2015) Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors. Journal of Inorganic Biochemistry, 153 68-87. doi:10.1016/j.jinorgbio.2015.09.014

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Author Fernandes, Christiane
Horn Jr, Adolfo
Lopes, Bruna F.
Bull, Erika S.
Azeredo, Nathália F.
Kanashiro, Milton M.
Borges, Franz V.
Bortoluzzi, Adailton J.
Szpoganicz, Bruno
Pires, Anderson B.
Franco, Roberto W. A.
de A. Almeida, João Carlos
Maciel, Leide L. F.
Resende, Jackson A. L. C.
Schenk, Gerhard
Title Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors
Formatted title
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 16.25 μmol dm- 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 55 mg kg- 1 was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50 = 14.5 mg kg- 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. 
Journal name Journal of Inorganic Biochemistry   Check publisher's open access policy
ISSN 0162-0134
1873-3344
Publication date 2015-12-01
Sub-type Article (original research)
DOI 10.1016/j.jinorgbio.2015.09.014
Open Access Status File (Author Post-print)
Volume 153
Start page 68
End page 87
Total pages 20
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Keyword Copper(II) complexes
X-ray diffraction studies
Apoptosis
THP-1
U937 and PBMC cells
Caspases
Mechanism of cell death
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 23 Oct 2015, 19:48:57 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences