Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
BioMetals Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abdi K, Hadadzadeh H, Weil M, Salimi M (2012a) Mononuclear copper(II) complex with terpyridine and an extended phenanthroline base, [Cu(tpy)(dppz)]2+: synthesis, crystal structure, DNA binding and cytotoxicity activity. Polyhedron 31:638–648

    Article  CAS  Google Scholar 

  • Abdi K, Hadadzadeh H, Salimi M, Simpson J, Khalaji AD (2012b) A mononuclear copper(II) complex based on the polypyridyl ligand 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz), [Cu(tptz)2]2+: X-ray crystal structure, DNA binding and in vitro cell cytotoxicity. Polyhedron 44:101–112

    Article  CAS  Google Scholar 

  • Bode AM, Dong Z (2009) Cancer prevention research then and now. Nat Rev Cancer 9:508–516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boerner LJK, Zaleski JM (2005) Metal complex-DNA interactions: from transcription inhibition to photoactivated cleavage. Curr Opin Chem Biol 9:35–144

    Article  Google Scholar 

  • Castonguay A, Doucet C, Juhas M, Maysinger D (2012) New ruthenium(II)-letrozole complexes as anticancer therapeutics. J Med Chem 55:8799–8806

    Article  CAS  PubMed  Google Scholar 

  • Chandra D, Liu JW, Tang DG (2002) Early mitochondrial activation and cytochrome c up-regulation during apoptosis. J Biol Chem 52:50842–50854

    Article  Google Scholar 

  • Daniel KG, Gupta P, Harbach RH, Guida WC, Dou QP (2004) Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells. Biochem Pharmacol 67:1139–1151

    Article  CAS  PubMed  Google Scholar 

  • De Miglio MR, Muroni MR, Simile MM, Calvisi DF, Tolu P, Deiana L, Carru A, Bonelli G, Feo F, Pascale RM (2000) Implication of Bcl-2 family genes in basal and D-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions. Hepatology 31:956–965

    Article  PubMed  Google Scholar 

  • Fei BL, Li W, Xu WS, Li YG, Long JY, Liu QB, Shao KZ, Su M, Sun WY (2013) Two novel copper complexes of 2,2′-bipyridine: evaluation of the DNA binding and cytotoxic activity. J Photochem Photobiol B 125:32–41

    Article  CAS  PubMed  Google Scholar 

  • 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 103:243–255

    Article  PubMed  Google Scholar 

  • Ghosh K, Kumar P, Tyagi N, Singh UP, Goel N, Chakraborty A, Roy P, Baratto MC (2011) DNA interaction, superoxide scavenging and cytotoxicity studies on new copper(II) complexes derived from a tridentate ligand. Polyhedron 30:2667–2677

    Article  CAS  Google Scholar 

  • Graham LA, Suryadi J, West TK, Kucera GL, Bierbach U (2012) Synthesis, aqueous reactivity, and biological evaluation of carboxylic acid ester-functionalized platinum-acridine hybrid anticancer agents. J Med Chem 55:7817–7827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gust R, Ott I, Posselt D, Sommer K (2004) Development of cobalt(3,4-diarylsalen) complexes as tumor therapeutics. J Med Chem 47:5837–5846

    Article  CAS  PubMed  Google Scholar 

  • Gutteridge JMC, Halliwell B (1982) The role of superoxide and hydroxyl radicals in the degradation of DNA and deoxyribose induced by a copper-phenanthroline complex. Biochem Pharmacol 31:2801–2805

    Article  CAS  PubMed  Google Scholar 

  • Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49

    Article  CAS  PubMed  Google Scholar 

  • Klinman JP (1996) Mechanisms whereby mononuclear copper proteins functionalize organic substrates. Chem Rev 96:2541–2561

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Kunita M, Nishino S, Matsushima H, Tokii T, Masuda H, Einaga H, Nishida Y (2000) Release of free nucleobases from oligomers by copper(II)-peroxide adduct. Polyhedron 19:2639–2648

    Article  CAS  Google Scholar 

  • Köpf-Maier P (1999) Antitumor activity of titanocene dichloride in xenografted human renal-cell carcinoma. Anticancer Res 19:493–504

    PubMed  Google Scholar 

  • Kumar P, Singh AK, Pandey R, Pandey DS (2011) Bio-catalysts and catalysts based on ruthenium(II) polypyridyl complexes imparting diphenyl-(2-pyridyl)-phosphine as a co-ligand. J Organomet Chem 696:3454–3464

    Article  CAS  Google Scholar 

  • Lacroix M, Leclercq G (2004) Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83:249–289

    Article  CAS  PubMed  Google Scholar 

  • Lee SY, Jeong SH, Kim YN, Kim J, Kang DR, Kim HC, Nam CM (2009) Cost-effective mammography screening in Korea: high incidence of breast cancer in young women. Cancer Sci 100:1105–1111

    Article  CAS  PubMed  Google Scholar 

  • Li DD, Tian JL, Gu W, Liu X, Zeng HH, Yan SP (2011) DNA binding, oxidative DNA cleavage, cytotoxicity, and apoptosis-inducing activity of copper(II) complexes with 1,4-tpbd (N,N,N′,N′-tetrakis(2-yridylmethyl)benzene-1,4-diamine) ligand. J Inorg Biochem 105:894–901

    Article  CAS  PubMed  Google Scholar 

  • Marzano C, Pellei M, Tisato F, Santini C (2009) Copper complexes as anticancer agents. Anti-Cancer Agents Med Chem 9:185–211

    Article  CAS  Google 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 66:10478–10486

    Article  CAS  PubMed  Google Scholar 

  • Ott I, Gust R (2007) Non platinum metal complexes as anti-cancer drugs. Arch Pharm 340:117–126

    Article  CAS  Google Scholar 

  • Pratt MA, White D, Kushwaha N, Tibbo E, Niu MY (2007) Cytoplasmic mutant p53 increases Bcl-2 expression in estrogen receptor-positive breast cancer cells. Apoptosis 12:657–669

    Article  CAS  PubMed  Google Scholar 

  • Raby BN, Polette M, Gilles C, Clavel C, Strumane K, Matos M, Zahm JM, Van Roy F, Bonnet N, Birembaut P (2001) Quantitative cell dispersion analysis: new test to measure tumor cell aggressiveness. Int J Cancer 93:644–652

    Article  CAS  Google 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 46:608–617

    Article  CAS  PubMed  Google 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 57:491–499

    Article  CAS  PubMed  Google Scholar 

  • Sigman DS, Graham DR, D’Aurora V, Stern AM (1979) Oxygen-dependent cleavage of DNA by the 1,10-phenanthroline.cuprous complex. Inhibition of Escherichia coli DNA polymerase I. J Biol Chem 254:12269–12272

    CAS  PubMed  Google Scholar 

  • Sigman DS, Mazumdar A, Perrin DM (1993) Chemical nucleases. Chem Rev 93:2295–2316

    Article  CAS  Google Scholar 

  • Song YL, Li YT, Wu ZY (2008) Synthesis, crystal structure, antibacterial assay and DNA binding activity of new binuclear Cu(II) complexes with bridging oxamidate. J Inorg Biochem 102:1691–1699

    Article  CAS  PubMed  Google Scholar 

  • Teijido O, Dejean L (2010) Upregulation of Bcl2 inhibits apoptosis-driven BAX insertion but favors BAX relocalization in mitochondria. FEBS Lett 584:3305–3310

    Article  CAS  PubMed  Google Scholar 

  • Top S, Kaloun EB, Vessières A, Laios I, Leclercq G, Jaouen G (2002) The first titanocenyl dichloride moiety vectorised by a selective estrogen receptor modulator (SERM). Synthesis and preliminary biochemical behavior. J Organomet Chem 634:350–356

    Article  Google Scholar 

  • Tu C, Shao Y, Gan N, Xu Q, Guo Z (2004) Oxidative DNA strand scission induced by a trinuclear copper(II) complex. Inorg Chem 43:4761–4766

    Article  CAS  PubMed  Google Scholar 

  • Uma Maheswari P, Palaniandavar M (2004a) DNA binding and cleavage properties of certain tetrammine ruthenium(II) complexes of modified 1,10-phenanthrolines—effect of hydrogen-bonding on DNA-binding affinity. J Inorg Biochem 98:219–230

    Article  CAS  PubMed  Google Scholar 

  • Uma Maheswari P, Palaniandavar M (2004b) DNA binding and cleavage activity of [Ru(NH3)4(diimine)]Cl2 complexes. Inorg Chim Acta 357:901–912

    Article  Google Scholar 

  • Yamamoto K, Kawanishi S (1989) Hydroxyl free radical is not the main active species in site-specific DNA damage induced by copper(II) ion and hydrogen peroxide. J Biol Chem 264:15435–15440

    CAS  PubMed  Google Scholar 

  • Zhang T, Chen X, Qu L, Wu J, Cui R, Zhao Y (2004) Chrysin and its phosphate ester inhibit cell. Bioorg Med Chem 12:6097–6105

    Article  CAS  PubMed  Google Scholar 

  • Zhang N, Kong X, Yan S, Yuan C, Yang O (2010) Huaier aqueous extract inhibits proliferation of breast cancer cells by inducing apoptosis. Cancer Sci 110:2375–2383

    Article  Google Scholar 

Download references

Acknowledgments

This study was financially supported by the Pasteur Institute of Iran and the Isfahan University of Technology (IUT).

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Pasteur Institute of Iran, P.O. Box 13164, 3159915111, Tehran, Iran

    Mona Salimi & Hirsa Mostafapour Kandelous

  2. Department of Chemistry, Isfahan University of Technology, 84156-83111, Isfahan, Iran

    Khatereh Abdi & Hassan Hadadzadeh

  3. Department of Virology, Pasteur Institute of Iran, 3159915111, Tehran, Iran

    Kayhan Azadmanesh

  4. National Cell Bank of Iran, Pasteur Institute of Iran, 3159915111, Tehran, Iran

    Amir Amanzadeh & Hassan Sanati

Authors
  1. Mona Salimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Khatereh Abdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirsa Mostafapour Kandelous
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hassan Hadadzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kayhan Azadmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amir Amanzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hassan Sanati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mona Salimi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salimi, M., Abdi, K., Kandelous, H.M. et al. Antiproliferative effects of copper(II)–polypyridyl complexes in breast cancer cells through inducing apoptosis. Biometals 28, 267–278 (2015). https://doi.org/10.1007/s10534-015-9820-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-015-9820-5

Keywords

Search

Navigation