Antiproliferative effects of copper(II)–polypyridyl complexes in breast cancer cells through inducing apoptosis
- 484 Downloads
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.
KeywordsCancer Apoptosis DNA cleavage Cytotoxicity
This study was financially supported by the Pasteur Institute of Iran and the Isfahan University of Technology (IUT).
- García-Giménez JL, Alzuet G, González-Álvarez M, Liu-González M, Castiñeiras A, Borrás J (2009) Oxidative nuclease activity of ferromagnetically coupled μ-hydroxo-μ-propionato copper(II) complexes [Cu3(L)2(μ-OH)2(μ-propionato)2] (L = N-(pyrid-2-ylmethyl)R-sulfonamidato, R = benzene, toluene, naphthalene). J Inorg Biochem 103:243–255CrossRefPubMedGoogle Scholar
- Milacic V, Chen D, Ronconi L, Landis-Piwowar KR, Fregona D, Dou QP (2006) A novel anticancer gold(III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts. Cancer Res 66:10478–10486CrossRefPubMedGoogle Scholar
- Rajalakshmi S, Weyhermüller T, Freddy AJ, Vasanthi HR, Nair BU (2011) Anomalous behavior of pentacoordinate copper complexes of dimethylphenanthroline and derivatives of terpyridine ligands: studies on DNA binding, cleavage and apoptotic activity. Eur J Med Chem 46:608–617CrossRefPubMedGoogle Scholar
- Serova M, Calvo F, Lokiec F, Koeppel F, Poindessous V, Larsen AK, Van Laar ES, Waters SJ, Cvitkovic E, Raymond E (2006) Characterizations of irofulven cytotoxicity in combination with cisplatin and oxaliplatin in human colon, breast, and ovarian cancer cells. Cancer Chemother Pharmacol 57:491–499CrossRefPubMedGoogle Scholar