Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells

Horn, Adolfo, Jr., Fernandes, Christiane, Parrilha, Gabrieli L., Kanashiro, Milton M., Borges, Franz V., de Melo, Edesio J. T., Schenk, Gerhard, Terenzi, Hernan and Pich, Claus T. (2013) Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells. Journal of Inorganic Biochemistry, 128 38-47. doi:10.1016/j.jinorgbio.2013.07.019


Author Horn, Adolfo, Jr.
Fernandes, Christiane
Parrilha, Gabrieli L.
Kanashiro, Milton M.
Borges, Franz V.
de Melo, Edesio J. T.
Schenk, Gerhard
Terenzi, Hernan
Pich, Claus T.
Title Highly efficient synthetic iron-dependent nucleases activate both intrinsic and extrinsic apoptotic death pathways in leukemia cancer cells
Journal name Journal of Inorganic Biochemistry   Check publisher's open access policy
ISSN 0162-0134
1873-3344
Publication date 2013-11-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.jinorgbio.2013.07.019
Open Access Status Not yet assessed
Volume 128
Start page 38
End page 47
Total pages 10
Place of publication Philadelphia, PA United States
Publisher Elsevier Inc.
Language eng
Subject 1303 Biochemistry
1604 Inorganic Chemistry
Abstract The nuclease activity and the cytotoxicity toward human leukemia cancer cells of iron complexes, [Fe(HPClNOL) Cl-2]NO3 (1), [Cl(HPClNOL)Fe(mu-O)Fe(HPClNOL)Cl]Cl-2 center dot 2H(2)O (2), and [(SO4)(HPCINOL)Fe(mu-O)Fe(HPCINOL)(SO4)]center dot 6H(2)O (3) (HPCINOL = 1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol), were investigated. Each complex was able to promote plasmid DNA cleavage and change the supercoiled form of the plasmid to circular and linear ones. Kinetic data revealed that (1), (2) and (3) increase the rate of DNA hydrolysis about 278, 192 and 339 million-fold, respectively. The activity of the complexes was inhibited by distamycin, indicating that they interact with the minor groove of the DNA. The cytotoxic activity of the complexes toward U937, HL-60, Jukart and THP-1 leukemia cancer cells was studied employing 3-(4,5-dimethythiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence and electronic transmission microscopies, flow cytometry and a cytochrome C release assay. Compound (2) has the highest activity toward cancer cells and is the least toxic for normal ones (i.e. peripheral blood mononuclear cells (PBMCs)). In contrast, compound (1) is the least active toward cancer cells but displays the highest toxicity toward normal cells. Transmission electronic microscopy indicates that cell death shows features typical of apoptotic cells, which was confirmed using the annexin V-FITC/PI (fluorescein isothiocyanate/propidium iodide) assay. Furthermore, our data demonstrate that at an early stage during the treatment with complex (2) mitochondria lose their transmembrane potential, resulting in cytochrome C release. A quantification of caspases 3,9 (intrinsic apoptosis pathway) and caspase 8 (extrinsic apoptosis pathway) indicated that both the intrinsic (via mitochondria) and extrinsic (via death receptors) pathways are involved in the apoptotic stimuli. (C) 2013 Elsevier Inc. All rights reserved.
Keyword Dinuclear mu oxo iron complex
Nuclease
Leukemia cancer cell
Intrinsic apoptosis pathway
Extrinsic apoptosis pathway
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID FT120100694
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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