title: Antiproliferative effects of copper(II)-polypyridyl complexes in breast cancer cells through inducing apoptosis.
abstract: 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.
authors: Department of Physiology and Pharmacology, Pasteur Institute of Iran, P.O. Box 13164, 3159915111, Tehran, Iran, salimimona@pasteur.ac.ir.
authors: Mona
authors: M
authors: Salimi
authors: Khatereh
authors: K
authors: Abdi
authors: Hirsa Mostafapour
authors: HM
authors: Kandelous
authors: Hassan
authors: H
authors: Hadadzadeh
authors: Kayhan
authors: K
authors: Azadmanesh
authors: Amir
authors: A
authors: Amanzadeh
authors: Hassan
authors: H
authors: Sanati
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms; D049109:Cell Proliferation; D048430:Cell Shape; D056831:Coordination Complexes / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry; D053837:DNA Cleavage; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D056831:Coordination Complexes; D011725:Pyridines; D003300:Copper