Reference - Detail
| RRC ID | 72635 |
|---|---|
| Author | Acilan C, Cevatemre B, Adiguzel Z, Karakas D, Ulukaya E, Ribeiro N, Correia I, Pessoa JC. |
| Title | Synthesis, biological characterization and evaluation of molecular mechanisms of novel copper complexes as anticancer agents. |
| Journal | Biochim Biophys Acta Gen Subj |
| Abstract |
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS AND GENERAL SIGNIFICANCE:These Cu-complexes, namely Cu(Sal-Gly)(pheamine), may be considered promising anticancer agents with activity in cancer cells even with deficient p53 status. |
| Volume | 1861(2) |
| Pages | 218-234 |
| Published | 2017-2-1 |
| DOI | 10.1016/j.bbagen.2016.10.014 |
| PII | S0304-4165(16)30389-0 |
| PMID | 27773706 |
| MeSH | A549 Cells Animals Annexin A5 / metabolism Antineoplastic Agents / chemistry* Antineoplastic Agents / pharmacology* Apoptosis / drug effects Caspase 3 / metabolism Caspase 7 / metabolism Cattle Cell Line, Tumor Copper / chemistry* DNA / metabolism DNA Damage / drug effects DNA Fragmentation / drug effects HCT116 Cells HeLa Cells Humans Membrane Potential, Mitochondrial / drug effects Reactive Oxygen Species / metabolism Tumor Suppressor Protein p53 / metabolism Up-Regulation / drug effects |
| IF | 3.422 |
| Resource | |
| Human and Animal Cells | HeLa |