Antiproliferative effects of copper(II)–polypyridyl complexes in breast cancer cells through inducing apoptosis

• DOI: 10.1007/s10534-015-9820-5
• Publication Date: 2015-02-11T13:56:12Z
• Authors: Mona Salimi; Khatereh Abdi; Hirsa Mostafapour...; Hassan Hadadzadeh; Kayhan Azadmanesh; Amir Amanzadeh; Hassan Sanati
• Keywords: 0301 basic medicine; 0303 health sciences; Pyridines; Antineoplastic Agents; Apoptosis; Breast Neoplasms; 7. Clean energy; 3. Good health; 03 medical and health sciences; Coordination Complexes; MCF-7 Cells; Humans; Female; DNA Cleavage; Drug Screening Assays, Antitumor; Apoptosis Regulatory Proteins; Cell Shape; Copper; Cell Proliferation; Signal Transduction

Although cisplatin has been used for decades to treat human cancer, some toxic side effects and resistance are observed. Previous investigations have suggested copper complexes as a novel class of tumor-cell apoptosis inducers. The present study aimed to evaluate the anti-breast cancer activities of two polypyridyl-based copper(II) complexes, [Cu(tpy)(dppz)](NO3)2 (1) and [Cu(tptz)2](NO3)2 (2) (tpy = 2,2':6',2″-terpyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine, tptz = 2,4,6-tris(2-pyridyl)-1,3,5-triazine), using human breast adenocarcinoma cell line (MCF-7). The ability of the complexes to cleave supercoiled DNA in the presence and absence of external agents was also examined. The apoptotic activities of the complexes were assessed using flow cytometry, fluorescence microscope and western blotting analysis. Our results indicated the high DNA affinity and nuclease activity of complexes 1 and 2. The cleavage mechanisms between the complexes and plasmid DNA are likely to involve a singlet oxygen or singlet oxygen-like entity as the reactive oxygen species. Complexes 1 and 2 also significantly inhibited the proliferation of MCF-7 cells in a dose-dependent manner (IC50 values = 4.57 and 1.98 μM at 24 h, respectively). Complex 2 remarkably induced MCF-7 cells to undergo apoptosis, which was demonstrated by cell morphology, annexin-V and propidium iodide staining. The caspase cascade was activated as shown by the proteolytic cleavage of caspase-3 after treatment of MCF-7 cells with complex 2. Additionally, complex 2 significantly increased the expression of the Bax-to-Bcl-2 ratio to induce apoptosis. In conclusion, these results revealed that complex 2 may be a potential and promising chemotherapeutic agent to treat breast cancer.