Synthesis, biological characterization and evaluation of molecular mechanisms of novel copper complexes as anticancer agents

To overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal-based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal-Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA,...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Biochimica et biophysica acta. General subjects Jg. 1861; H. 2; S. 218 - 234
Hauptverfasser:	Acilan, Ceyda, Cevatemre, Buse, Adiguzel, Zelal, Karakas, Didem, Ulukaya, Engin, Ribeiro, Nádia, Correia, Isabel, Pessoa, João Costa
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Netherlands Elsevier B.V 01.02.2017
Schlagworte:	A549 Cells agarose Animals Annexin A5 - metabolism Anti-cancer drugs Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology apoptosis Apoptosis - drug effects binding capacity Caspase 3 - metabolism Caspase 7 - metabolism caspases Cattle Cell Line, Tumor circular dichroism spectroscopy cisplatin copper Copper - chemistry Copper complexes cytotoxicity DNA - metabolism DNA damage DNA Damage - drug effects DNA Fragmentation - drug effects drug therapy fluorescence gel electrophoresis HCT116 Cells HeLa Cells Humans Interactions with DNA Mechanism of cytotoxicity of Cu-compounds membrane potential Membrane Potential, Mitochondrial - drug effects mitochondrial membrane neoplasm cells neoplasms Phenanthroline phenotype quantitative polymerase chain reaction reactive oxygen species Reactive Oxygen Species - metabolism reverse transcriptase polymerase chain reaction Schiff base compounds staining supercoiled DNA Tumor Suppressor Protein p53 - metabolism Up-Regulation - drug effects Mechanism of cytotoxicity of Cu-compounds Schiff base compounds Phenanthroline Interactions with DNA Anti-cancer drugs Copper complexes
ISSN:	0304-4165, 1872-8006
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	To overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal-based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal-Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA, cytotoxicity and mechanism of action. The binding ability of the complexes to Calf-Thymus DNA was evaluated by competition fluorescence studies with thiazole-orange, UV–Vis and circular dichroism spectroscopic titrations. Cytotoxicity was evaluated by MTT analysis. The DNA damage was analyzed through cleavage of supercoiled DNA via agarose gel-electrophoresis, and 8-oxo-guanidine and ɣH2AX staining in cells. Apoptosis was detected via DNA condensation/fragmentation, mitochondrial membrane potential, Annexin V staining and caspase 3/7 activity. Formation of reactive oxygen species was determined by DCFDA- and GSSG/GSH-analysis. Binding constants to DNA were evaluated as 1.7×106 (Cu(Sal-Gly)(phen)), 2.5×106 (Cu(Sal-Gly)(pheamine)) and 3.2×105 (Cu(Sal-Gly)(phepoxy)). All compounds induced DNA damage. Apoptosis was the main form of cell death. There was an increase in ROS, which is most likely responsible for the observed DNA-damage. Although the compounds were cytotoxic to all tested cancer cell lines, only Cu(Sal-Gly)(pheamine) displayed significantly lower toxicity towards non-cancer cells, its associated phenotypes differing from the other two Cu-complexes. Thus, Cu(Sal-Gly)(pheamine) was further assayed for molecular changes in response to drug treatment using a custom designed RT-qPCR array. Results showed that Harakiri was significantly upregulated. Presence of p53 was not required for apoptosis in response to Cu-complexes. These Cu-complexes, namely Cu(Sal-Gly)(pheamine), may be considered promising anticancer agents with activity in cancer cells even with deficient p53 status. [Display omitted] •Three copper(II) complexes are synthesized and characterized.•Cu(Sal-Gly)(pheamine) is the most specific complex towards cancer cells.•The main mechanism of cell death is apoptosis.•All complexes bind to DNA and induce oxidative damage.•Harakiri is significantly upregulated in response to Cu(Sal-Gly)(pheamine).
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-4165 1872-8006
DOI:	10.1016/j.bbagen.2016.10.014