, Volume 31, Issue 2, pp 233–242 | Cite as

The cytotoxicity effects of a novel Cu complex on MCF-7 human breast cancerous cells

  • Fatemeh Mohammadizadeh
  • Soudeh Khanamani Falahati-pour
  • Azadeh Rezaei
  • Maryam Mohamadi
  • Mohammad Reza Hajizadeh
  • Mohammad Reza Mirzaei
  • Alireza Khoshdel
  • Mohammad Ali Fahmidehkar
  • Mehdi MahmoodiEmail author


A variety of biological activities, such as anti-microbial and anti-tumor properties was reported for 1,10-phenanthroline and its copper complexes. In this study, the anti-proliferative activity of a novel  [Cu(L)(phen)] complex was investigated on MCF-7 breast cancer cells using MTT assay. Since chemotherapy is lake of ability to distinguish between normal cells from cancerous cells, therefore we also investigated the effect of  [Cu(L)(phen)] complex on normal L929 cells. The results showed that following 24 and 48 h exposure of cells with  [Cu(L)(phen)] complex, the IC50 values for MCF-7 were significantly lower than that recorded for L929 and normal cells were less sensitive than cancerous cells to the complex. Additionally, the  [Cu(L)(phen)] complex displayed a time- and concentration-dependent cytotoxic response, with MCF-7 and L929 cells. Also flow cytometry findings suggest that  [Cu(L)(phen)] complex is capable of decreasing cancer cell viability through apoptosis and did not efficiently activate the necrosis process.


Apoptosis Breast cancer  [Cu(L)(phen)] complex Cytotoxicity MCF-7 cell line 



Dimethyl sulfoxide


Fetal bovine serum


Fluorescein isothiocyanate


Inhibiting cell growth by 50%


3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide


Phosphate buffered saline


Propidium iodide


Statistical package for the social sciences




World Health Organization



This article is an excerpt from Fatemeh Mohammadizadeh’s master’s thesis in Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences (RUMS), Rafsanjan, Iran. The authors would like to thank the Molecular Medicine Research Center (MMRC) in RUMS from of Iran for providing the necessary equipment for this work. This study was approved by the RUMS Ethical Committee by the Number of IR.RUMS.REC.1395.140.


This study was supported by the RUMS by the Grant Number 20.1326.

Compliance with ethical standards

Conflict of interest

The authors report no Conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

This article does not contain any studies with human participants.


  1. Adams J (2003) Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today 8:307–315CrossRefPubMedGoogle Scholar
  2. Almond J, Cohen G (2002) The proteasome: a novel target for cancer chemotherapy. Leukemia 16:433CrossRefPubMedGoogle Scholar
  3. Banerjee S, Chakravarty AR (2015) Metal complexes of curcumin for cellular imaging, targeting, and photoinduced anticancer activity. Acc Chem Res 48:2075–2083CrossRefPubMedGoogle Scholar
  4. Bravo-Gómez ME, García-Ramos JC, Gracia-Mora I, Ruiz-Azuara L (2009) Antiproliferative activity and qsar study of copper (ii) mixed chelate [cu (n–n)(acetylacetonato)] no 3 and [cu (n–n)(glycinato)] no 3 complexes,(casiopeínas®). J Inorg Biochem 103:299–309CrossRefPubMedGoogle Scholar
  5. Carvallo-Chaigneau F et al (2008) Casiopeina III-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo. Biometals 21:17–28CrossRefPubMedGoogle Scholar
  6. Chen D, Frezza M, Shakya R, Cui QC, Milacic V, Verani CN, Dou QP (2007) Inhibition of the proteasome activity by gallium (III) complexes contributes to their anti–prostate tumor effects. Can Res 67:9258–9265CrossRefGoogle Scholar
  7. Correia I et al (2015) Vanadium (IV) and copper (II) complexes of salicylaldimines and aromatic heterocycles: cytotoxicity. DNA Bind DNA Cleavage Prop J Inorg Biochem 147:134–146CrossRefGoogle Scholar
  8. Devereux M et al (2006) Synthesis, superoxide dismutase mimetic and anticancer activities of metal complexes of 2, 2-Dimethylpentanedioic acid (2dmepdaH2) and 3, 3-Dimethylpentanedioic acid (3dmepdaH2): x-ray crystal structures of [Cu (3dmepda)(bipy)] 2· 6H2O and [Cu (2dmepda)(bipy)(EtOH)] 2· 4EtOH (bipy = 2, 2′ Bipyridine). Bioinorg Chem Appl.
  9. De Vizcaya-Ruiz A, Rivero-Muller A, Ruiz-Ramirez L, Kass G, Kelland L, Orr R, Dobrota M (2000) Induction of apoptosis by a novel copper-based anticancer compound, casiopeina II, in L1210 murine leukaemia and CH1 human ovarian carcinoma cells. Toxicol Vitro 14:1–5CrossRefGoogle Scholar
  10. Deegan C, Coyle B, McCann M, Devereux M, Egan DA (2006) In vitro anti-tumour effect of 1, 10-phenanthroline-5, 6-dione (phendione),[Cu (phendione) 3](ClO 4) 2· 4H 2 O and [Ag (phendione) 2] ClO 4 using human epithelial cell lines. Chem Biol Interact 164:115–125CrossRefPubMedGoogle Scholar
  11. Deegan C, McCann M, Devereux M, Coyle B, Egan DA (2007) In vitro cancer chemotherapeutic activity of 1, 10-phenanthroline (phen),[Ag 2 (phen) 3 (mal)]·2H 2 O,[Cu (phen) 2 (mal)]·2H 2 O and [Mn (phen) 2 (mal)]· 2H 2 O (malH 2 = malonic acid) using human cancer cells. Cancer Lett 247:224–233CrossRefPubMedGoogle Scholar
  12. Fan L, Tian M, Liu Y, Deng Y, Liao Z, Xu J (2017) Salicylate• Phenanthroline copper (II) complex induces apoptosis in triple-negative breast cancer cells. Oncotarget 8:29823Google Scholar
  13. Gan Q, Fu X, Chen W, Xiong Y, Fu Y, Chen S, Le X (2016) Synthesis, DNA/HSA interaction spectroscopic studies and in vitro cytotoxicity of a new mixed ligand Cu (II) complex. J Fluoresc 26:905–918CrossRefPubMedGoogle Scholar
  14. Geraghty M, Sheridan V, McCann M, Devereux M, McKee V (1999) Synthesis and anti-Candida activity of copper (II) and manganese (II) carboxylate complexes: x-ray crystal structures of [Cu (sal)(bipy)]· C2H5OH· H2O and [Cu (norb)(phen) 2]· 6.5 H2O (salH2 = salicylic acid; norbH2 = cis-5-norbornene-endo-2, 3-dicarboxylic acid; bipy = 2, 2′-bipyridine; phen = 1, 10-phenanthroline). Polyhedron 18:2931–2939CrossRefGoogle Scholar
  15. González SEF, Anguiano EA, Herrera AM, Calzada DE, Pichardo CO (2013) Cytotoxic, pro-apoptotic, pro-oxidant, and non-genotoxic activities of a novel copper (II) complex against human cervical cancer. Toxicology 314:155–165CrossRefGoogle Scholar
  16. Green DR, Reed JC (1998) Mitochondria and apoptosis. Sci-AAAS-Weekly Pap Edition 281:1309–1311Google Scholar
  17. Hajrezaie M et al (2014) A Schiff Base-derived copper (II) complex is a potent inducer of apoptosis in colon cancer cells by activating the intrinsic pathway. The Scientific World Journal 2014Google Scholar
  18. Harris ZL, Gitlin JD (1996) Genetic and molecular basis for copper toxicity. Am J Clin Nutr 63:836S–841SCrossRefPubMedGoogle Scholar
  19. Hosseini FS et al (2017) Persian shallot, Allium hirtifolium Boiss, induced apoptosis in human hepatocellular carcinoma cells. Cytotechnology 69:551–563CrossRefPubMedGoogle Scholar
  20. Jaividhya P, Dhivya R, Akbarsha MA, Palaniandavar M (2012) Efficient DNA cleavage mediated by mononuclear mixed ligand copper (II) phenolate complexes: the role of co-ligand planarity on DNA binding and cleavage and anticancer activity. J Inorg Biochem 114:94–105CrossRefPubMedGoogle Scholar
  21. Johnstone TC, Park GY, Lippard SJ (2014) Understanding and improving platinum anticancer drugs–phenanthriplatin. Anticancer Res 34:471–476PubMedPubMedCentralGoogle Scholar
  22. Karimabad MN et al (2017) The novel indole-3-formaldehyde (2-AITFEI-3-F) is involved in processes of apoptosis induction? Life Sci 181:31–44Google Scholar
  23. 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 100:1105–1111CrossRefPubMedGoogle Scholar
  24. Ma T et al (2015) Ternary copper (II) complexes with amino acid chains and heterocyclic bases: DNA binding, cytotoxic and cell apoptosis induction properties. J Inorg Biochem 144:38–46CrossRefPubMedGoogle Scholar
  25. Majeed W, Aslam B, Javed I, Khaliq T, Muhammad F, Ali A, Raza A (2014) Breast cancer: major risk factors and recent developments in treatment. Asian Pac J Cancer Prev 15:3353–3358CrossRefPubMedGoogle Scholar
  26. Norbury CJ, Hickson ID (2001) Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 41:367–401CrossRefPubMedGoogle Scholar
  27. Ott I, Gust R (2007) Non platinum metal complexes as anti-cancer drugs. Arch der Pharm 340:117–126CrossRefGoogle Scholar
  28. Płotek M, Dudek K, Kyzioł A (2013) Selected copper (I) complexes as potential anticancer agent. Chemik 67(12):11–15Google Scholar
  29. Ramezani M et al (2017) Does the Novel Class of (2R, 4S)-N-(2, 5-Difluorophenyl)-4-Hydroxy-1-(2, 2, 2-Trifluoroacetyl) Pyrrolidine-2-Carboxamide’s have any effect on cell viability and apoptosis of human hepatocellular carcinoma cells? Int J Cancer Manag 10:e8413CrossRefGoogle Scholar
  30. Ranford JD, Sadler PJ, Tocher DA (1993) Cytotoxicity and antiviral activity of transition-metal salicylato complexes and crystal structure of bis (diisopropylsalicylato)(1, 10-phenanthroline) copper (II). J Chem Soc Dalton Trans 22:3393–3399Google Scholar
  31. Ruiz-Azuara L, E Bravo-Gomez M (2010) Copper compounds in cancer chemotherapy. Curr Med Chem 17:3606–3615CrossRefPubMedGoogle Scholar
  32. Santini C, Pellei M, Gandin V, Porchia M, Tisato F, Marzano C (2013) Advances in copper complexes as anticancer agents. Chem Rev 114:815–862CrossRefPubMedGoogle Scholar
  33. Sheikhrezaei Z et al (2018) A new indole derivative decreased SALL4 gene expression in acute promyelocytic leukemia cell line (NB4). Iran Biomed J 22:92–106Google Scholar
  34. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics. 2015 CA Cancer J Clin 65:5–29CrossRefPubMedGoogle Scholar
  35. Takjoo R, Mague JT, Akbari A, Ebrahimipour SY (2013) Synthesis, structural, and thermal analyses of copper (II) and oxido-vanadium (IV) complexes of 4-bromo-2-(((5-chloro-2-hydroxyphenyl) imino) methyl) phenol. J Coord Chem 66:2852–2862CrossRefGoogle Scholar
  36. Takjoo R, Akbari A, Ebrahimipour SY, Rrudbari HA, Brunò G (2014) Synthesis, characterization, X-ray structure and DFT calculation of two Mo (VI) and Ni (II) Schiff-base complexes. C R Chim 17:1144–1153CrossRefGoogle Scholar
  37. Trejo-Solís C et al (2005) Cas ilgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms. Neoplasia 7:563–574CrossRefPubMedPubMedCentralGoogle Scholar
  38. Wang T et al (2016) Copper ion attenuated the antiproliferative activity of Di-2-pyridylhydrazone dithiocarbamate derivative; however, there was a lack of correlation between ROS generation and antiproliferative activity. Molecules 21:1088CrossRefGoogle Scholar
  39. Yu H et al (2016) Ternary dinuclear copper (II) complexes of a reduced schiff base ligand with diimine coligands: DNA binding, cytotoxic cell apoptosis, and apoptotic mechanism. Chem Biol Drug Des 87:398–408CrossRefPubMedGoogle Scholar
  40. Zhang CX, Lippard SJ (2003) New metal complexes as potential therapeutics. Curr Opin Chem Biol 7:481–489CrossRefPubMedGoogle Scholar
  41. Zoroddu MA, Zanetti S, Pogni R, Basosi R (1996) An electron spin resonance study and antimicrobial activity of copper(II)-phenanthroline complexes. J Inorg Biochem 63:291–300CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fatemeh Mohammadizadeh
    • 1
    • 2
  • Soudeh Khanamani Falahati-pour
    • 2
  • Azadeh Rezaei
    • 1
    • 3
  • Maryam Mohamadi
    • 2
  • Mohammad Reza Hajizadeh
    • 1
    • 3
  • Mohammad Reza Mirzaei
    • 1
    • 3
  • Alireza Khoshdel
    • 1
    • 2
  • Mohammad Ali Fahmidehkar
    • 4
  • Mehdi Mahmoodi
    • 3
    • 5
    Email author
  1. 1.Department of Clinical Biochemistry, Faculty of MedicineRafsanjan University of Medical SciencesRafsanjanIran
  2. 2.Pistachio Safety Research CenterRafsanjan University of Medical SciencesRafsanjanIran
  3. 3.Molecular Medicine Research CenterRafsanjan University of Medical SciencesRafsanjanIran
  4. 4.Research Center of Advanced Technologies in MedicineTorbat Heydariyeh University of Medical SciencesTorbat HeydariyehIran
  5. 5.Department of Clinical Biochemistry, Afzalipoor Faculty of MedicineKerman University of Medical SciencesKermanIran

Personalised recommendations