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In Vitro Anticancer Activity of Novel Co(II) and Ni(II) Complexes of Non-steroidal Anti-inflammatory Drug Niflumic Acid Against Human Breast Adenocarcinoma MCF-7 Cells

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Abstract

Herein, we report the synthesis, characterization and anticancer activity of six novel complexes of non-steroidal anti-inflammatory drug niflumic acid with Co(II) and Ni(II). In vitro cytotoxicity screening in MCF-7, HepG2 and HT-29 cancer cell lines showed that the complex 3 [Co(nif)2(met)(4-pic)] and complex 6 [Ni(nif)2(met)(4-pic)] among all the complexes exhibited the highest cytotoxicity against MCF-7 cells with IC50 values of 11.14 µM and, 41.47 µM, respectively. Besides, all the complexes exhibited significantly higher selectivity towards mouse fibroblast 3T3L1 cells. Further mechanistic studies with both complexes on MCF-7 cells revealed their cytotoxic action through the mitochondrial-dependent apoptotic pathway causing an increase oxidative/nitrosative stress, decrease in mitochondrial membrane potential (ΔΨm), inducing the multicaspase activation and arresting the cell cycle at S phase. q-PCR analysis resulted in an increase in the expression of the apoptotic marker proteins bax, p53 and caspase-3 and -8 in MCF-7 cells, but a decrease in the expression of antiapoptotic bcl-2 gene. Moreover, both complexes induced the apoptosis through the inhibition of PI3K/Akt signaling pathway by decreasing the expression of PI3K and increasing dephosphorylation form of Akt protein. These results provide a significant contribution to the explanation of the anticancer mechanisms of these complexes in MCF-7 cells.

Highlights

  • Novel Co(II) and Ni(II) complexes were synthesized and characterized by FT-IR, elemental and thermal analysis techniques.

  • Complex 3 showed the highest cytotoxic activity against MCF-7, HT-29, and HepG2 cells.

  • Complex 3 and 6 triggered the apoptosis by inducing oxidative stress in MCF-7 cells.

  • Complex 3 and 6 deactivated the PI3K/Akt pathway in MCF-7 cells.

  • Complex 3 and 6 modulated the apoptotic marker genes: bax, bcl-2, p53, caspase-3 and -8 in MCF-7 cells.

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References

  1. Rosenberg, B. (1980). Cisplatin: its history and possible mechanisms of action. Academic Press: Inc. https://doi.org/10.1016/b978-0-12-565050-2.50006-1.

  2. Benedetti, B. T., Peterson, E. J., Kabolizadeh, P., Martínez, A., Kipping, R., & Farrell, N. P. (2011). Effects of noncovalent platinum drug-protein interactions on drug efficacy: use of fluorescent conjugates as probes for drug metabolism. Molecular Pharmaceutics, 8, 940–948. https://doi.org/10.1021/mp2000583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bhargava, A., & Vaishampayan, U. N. (2009). Satraplatin: leading the new generation of oral platinum agents. Expert Opinion on Investigational Drugs, 18, 1787–1797. https://doi.org/10.1517/13543780903362437.

    Article  CAS  PubMed  Google Scholar 

  4. Frezza, M., Hindo, S., Chen, D., Davenport, A., Schmitt, S., Tomco, D., & Ping Dou, Q. (2010). Novel metals and metal complexes as platforms for cancer therapy. Current Pharmaceutical Design, 16, 1813–1825. https://doi.org/10.2174/138161210791209009.

    Article  CAS  PubMed Central  Google Scholar 

  5. Karlenius, T. C., & Tonissen, K. F. (2010). Thioredoxin and cancer: a role for thioredoxin in all states of tumor oxygenation. Cancers (Basel), 2, 209–232. https://doi.org/10.3390/cancers2020209.

    Article  CAS  Google Scholar 

  6. Bindoli, A., Pia, M., Scutari, G., Gabbiani, C., Casini, A., Messori, L., Thioredoxin reductase: a target for gold compounds acting as potential anticancer drugs, 253 (2009) 1692–1707. https://doi.org/10.1016/j.ccr.2009.02.026.

  7. Gupte, A., & Mumper, R. J. (2009). Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews, 35, 32–46. https://doi.org/10.1016/j.ctrv.2008.07.004.

    Article  CAS  PubMed  Google Scholar 

  8. Monneret, C. (2011). Platinum anticancer drugs. From serendipity to. Annales Pharmaceutiques Françaises, 69, 286–295. https://doi.org/10.1016/j.pharma.2011.10.001.

    Article  CAS  PubMed  Google Scholar 

  9. Johnstone, T. C., Suntharalingam, K., Lippard, S. J., The next generation of platinum drugs: targeted Pt (II) agents, nanoparticle delivery, and Pt (IV) prodrugs, (2016). https://doi.org/10.1021/acs.chemrev.5b00597.

  10. Kumazawa, S., Hamasaka, T., & Nakayama, T. (2004). Antioxidant activity of propolis of various geographic origins. Food Chemistry, 84, 329–339.

    Article  CAS  Google Scholar 

  11. Mi, Q., Ma, Y., Gao, X., Liu, R., Liu, P., Mi, Y., Fu, X., 2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity, 1102 (2016). https://doi.org/10.1080/07391102.2015.1114972.

  12. Du, C. P. V., Elliott, C. J., Connor, R. A. O., Heenan, M. M., Coyle, S., Cleary, I. M., Kavanagh, K., Verhaegen, S., Loughlin, C. M. O., Nicamhlaoibh, R., & Clynes, M. (1998). Original paper enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory Drugs (NSAIDs). European Journal of Cancer, 34, 1250–1259.

    Article  Google Scholar 

  13. Zianna, A., Ristovic, M. S., Psomas, G., Hatzidimitriou, A., Coutouli-Argyropoulou, E., & Lalia-Kantouri, M. (2015). Cadmium(II) complexes of 5-nitro-salicylaldehyde and α-diimines: synthesis, structure and interaction with calf-thymus DNA. Journal of Coordination Chemistry, 68, 4444–4463. https://doi.org/10.1080/00958972.2015.1101075.

    Article  CAS  Google Scholar 

  14. Zampakou, M., Hatzidimitriou, A. G., Athanasios, N., & Psomas, G. (2015). Neutral and cationic manganese (II)–diclofenac complexes: structure and biological evaluation. Journal of Coordination Chemistry, 68, 4355–4372. https://doi.org/10.1080/00958972.2015.1098633.

    Article  CAS  Google Scholar 

  15. Johnsen, J. I., Lindskog, M., Ponthan, F., Pettersen, I. (2005) NSAIDs in neuroblastoma therapy, 228, 195–201. https://doi.org/10.1016/j.canlet.2005.01.058.

  16. Amin, A. R., Vyas, P., Atrur, M., Leszczynska-pizlak, J., Patelt, I. R., Weissmann, G., & Abramson, S. B. (1995). The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Medical Sciences, 92, 7926–7930.

    CAS  Google Scholar 

  17. Rao, P. N. P., Knaus, E. E., Road, T. P., & Jolla, L. (2008). Evolution of nonsteroidal anti-inflammatory cyclooxygenase (COX) inhibition and beyond drugs (NSAIDs). Journal of Pharmaceutical Sciences, 11, 81–110.

    Google Scholar 

  18. Basha, R., Ahmad, S., Safe, S., & Abbruzzese, J. L. (2011). Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid. Frontiers in Bioscience-Scholar, 3, 797–805. https://doi.org/10.2741/S188.

    Article  Google Scholar 

  19. Gasparini, L., Ongini, E., Wenk, G., Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer ’ s disease: old and new mechanisms of action, (2004) 521–536. https://doi.org/10.1111/j.1471-4159.2004.02743.x.

  20. Ho Woo, D., Han, I. S., & Jung, G. (2004). Mefenamic acid-induced apoptosis in human liver cancer cell-lines through caspase-3 pathway. Life Sciences., 75, 2439–2449. https://doi.org/10.1016/j.lfs.2004.04.042.

    Article  CAS  Google Scholar 

  21. Tarushi, A., Kara, Z., Kljun, J., Turel, I., Psomas, G., Papadopoulos, A. N., Kessissoglou, D. P., Antioxidant capacity and DNA-interaction studies of zinc complexes with a non-steroidal anti-inflammatory drug, mefenamic acid, 128 (2013) 85–96. https://doi.org/10.1016/j.jinorgbio.2013.07.013.

  22. Tsiliki, P., Perdih, F., Turel, I., & Psomas, G. (2013). Structure, DNA- and albumin-binding of the manganese (II) complex with the non-steroidal antiinflammatory drug niflumic acid. Polyhedron., 53, 215–222. https://doi.org/10.1016/j.poly.2013.01.049.

    Article  CAS  Google Scholar 

  23. Palacios-hernández, T., Höp, H., Sánchez-salas, J. L., González-vergara, E., & Pérez-benítez, A. (2014). In vitro antibacterial activity of meclofenamate metal complexes with Cd (II) Pb (II), Co (II), and Cu (II). Crystal Structures of,139, 85–92. https://doi.org/10.1016/j.jinorgbio.2014.06.008.

    Article  CAS  Google Scholar 

  24. Ma, Z., & Moulton, B. (2011). Recent advances of discrete coordination complexes and coordination polymers in drug delivery. Coordination Chemistry Reviews, 255, 1623–1641. https://doi.org/10.1016/j.ccr.2011.01.031.

    Article  CAS  Google Scholar 

  25. Knauf, P. A., & Mann, N. A. (1984). Use of niflumic acid to determine the nature of the asymmetry of the human erythrocyte anion exchange system. Journal of General Physiology, 83, 703–725. https://doi.org/10.1085/jgp.83.5.703.

    Article  CAS  Google Scholar 

  26. Sinkkonen, S., Mansikkamaki, S., Möykkynen, T., & Lüddens, H. (2003). Receptor subtype-dependent positive and negative modulation of GABAA receptor function by niflumic acid, a nonsteroidal anti-inflammatory drug. Molecular Pharmacology, 64, 753–763.

    Article  CAS  Google Scholar 

  27. Balderas, E., Ateaga-tlecuitl, R., Rivera, M., Gomora, J. C., Darszon, A., Niflumic acid blocks native and recombinant T-type channels, (n.d.). https://doi.org/10.1002/jcp.22992.

  28. Kumar, S., Pal, R., Venugopalan, P., Ferretti, V., & Tarpin, M. (2019). Inorganica chimica acta new copper (II) niflumate complexes with N-donor ligands: synthesis, characterization and evaluation of anticancer potential against human cell lines. Inorganica Chimica Acta, 488, 260–268. https://doi.org/10.1016/j.ica.2019.01.020.

    Article  CAS  Google Scholar 

  29. Kim, B. M., Maeng, K., Lee, K. H., & Hong, S. H. (2011). Combined treatment with the Cox-2 inhibitor niflumic acid and PPARγ ligand ciglitazone induces ER stress/caspase-8-mediated apoptosis in human lung cancer cells. Cancer Letters, 300, 134–144. https://doi.org/10.1016/j.canlet.2010.09.014.

    Article  CAS  PubMed  Google Scholar 

  30. Smolko, L., Smolková, R., Samoľová, E., Morgan, I., Saoud, M., & Kaluđerović, G. N. (2020). Two isostructural Co (II) flufenamato and niflumato complexes with bathocuproine: analogues with a different cytotoxic activity. Journal of Inorganic Biochemistry., 210, 111160 https://doi.org/10.1016/j.jinorgbio.2020.111160.

    Article  CAS  PubMed  Google Scholar 

  31. Tarushi, A., Raptopoulou, C. P., Psycharis, V., Kessissoglou, D. P., Papadopoulos, A. N., Psomas, G., Interaction of zinc (II) with the non-steroidal anti-in fl ammatory drug niflumic acid, 176 (2017) 100–112. https://doi.org/10.1016/j.jinorgbio.2017.08.022.

  32. Altay, A., Caglar, S., & Caglar, B. (2019). Silver(I) complexes containing diclofenac and niflumic acid induce apoptosis in human-derived cancer cell lines. Archives of Physiology and Biochemistry, 0, 1–11. https://doi.org/10.1080/13813455.2019.1662454.

    Article  CAS  Google Scholar 

  33. Kefala, L., Hatzidimitriou, A. G., Kessissoglou, D. P., Perdih, F., Cobalt (II) complexes with non-steroidal anti-inflammatory drugs and α -diimines, 160 (2016) 125–139. https://doi.org/10.1016/j.jinorgbio.2015.12.015.

  34. Skyrianou, K. C., Efthimiadou, E. K., Psycharis, V., Terzis, A., Kessissoglou, D. P., & Psomas, G. (2009). Nickel – quinolones interaction . Part 1 – Nickel (II) complexes with the antibacterial drug sparfloxacin: Structure and biological properties. Journal of Inorganic Biochemistry, 103, 1617–1625. https://doi.org/10.1016/j.jinorgbio.2009.08.011.

    Article  CAS  PubMed  Google Scholar 

  35. Ramírez-macías, I., Maldonado, C. R., Marín, C., Olmo, F., Gutiérrez-sánchez, R., Rosales, M. J., Quirós, M., Salas, J. M., & Sánchez-moreno, M. (2012). In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis. Journal of Inorganic Biochemistry, 112, 1–9. https://doi.org/10.1016/j.jinorgbio.2012.02.025.

    Article  CAS  PubMed  Google Scholar 

  36. Skyrianou, K. C., Perdih, F., Papadopoulos, A. N., Turel, I., Kessissoglou, D. P., & Psomas, G. (2011). Nickel—quinolones interaction Part 5—Biological evaluation of nickel (II) complexes with fi rst-, second- and third-generation quinolones (A). Journal of Inorganic Biochemistry, 105, 1273–1285. https://doi.org/10.1016/j.jinorgbio.2011.06.005.

    Article  CAS  PubMed  Google Scholar 

  37. Dimiza, F., Papadopoulos, A. N., Tangoulis, V., Psycharis, V., Raptopoulou, C. P., Kessissoglou, D. P., & Psomas, G. (2012). Biological evaluation of cobalt (II) complexes with non-steroidal anti-in fl ammatory drug naproxen. Journal of Inorganic Biochemistry, 107, 54–64. https://doi.org/10.1016/j.jinorgbio.2011.10.014.

    Article  CAS  PubMed  Google Scholar 

  38. London, M. E., Lo, H., Gracia-mora, I., Poblano-mele, I., Barba-behrens, N., Synthesis, structure and biological activities of cobalt (II) and zinc (II) coordination compounds with 2-benzimidazole derivatives, 102 (2008) 1267–1276. https://doi.org/10.1016/j.jinorgbio.2008.01.016.

  39. Bisceglie, F., Pinelli, S., Alinovi, R., Goldoni, M., Mutti, A., Camerini, A., Piola, L., Tarasconi, P., & Pelosi, G. (2014). Cinnamaldehyde and cuminaldehyde thiosemicarbazones and their copper (II) and nickel (II) complexes: A study to understand their biological activity. Journal of Inorganic Biochemistry, 140, 111–125. https://doi.org/10.1016/j.jinorgbio.2014.07.014.

    Article  CAS  PubMed  Google Scholar 

  40. Prabu, R., Vijayaraj, A., Suresh, R., Senbhagaraman, R., Kaviyarasan, V., Biological studies of macrobicyclic binuclear nickel (II) complexes of 1, 8-difunctionalized cyclam derivatives, 8972 (2013). https://doi.org/10.1080/00958972.2012.751488.

  41. Ii, N., Jin, Y., Lewis, M. A., Gokhale, N. H., Long, E. C., & Cowan, J. A. (2007). Influence of Stereochemistry and Redox Potentials on the Single- and Double-Strand DNA Cleavage Efficiency of Cu(II)· and Ni(II)·Lys-Gly-His-Derived ATCUN Metallopeptides. American Chemical Society, 129, 8353–8361. https://doi.org/10.1021/ja0705083.

    Article  CAS  Google Scholar 

  42. Barone, G., Gambino, N., Ruggirello, A., Silvestri, A., Terenzi, A., & Turco, V. (2009). Spectroscopic study of the interaction of Ni II -5-triethyl ammonium methyl salicylidene ortho-phenylendiiminate with native DNA. Journal of Inorganic Biochemistry, 103, 731–737. https://doi.org/10.1016/j.jinorgbio.2009.01.006.

    Article  CAS  PubMed  Google Scholar 

  43. Moro, A. C., Urbaczek, A. C., De Almeida, E.T., Fernando, R., Leite, C. Q. F., Netto, A. V. G., Mauro, A. E., Moro, A. C., Urbaczek, A. C., De Almeida, E.T., Pavan, R., Leite, C. Q. F., Netto, A. V. G., Binuclear, Binuclear cyclopalladated compounds with antitubercular activity: synthesis and characterization of [{ Pd (C, N-dmba)(X)} 2 (µ -bpp)] (X = Cl, Br, NCO, N 3; bpp = 1, 3-bis (4-pyridyl) propane), 8972 (2012). https://doi.org/10.1080/00958972.2012.673718.

  44. Mascaliovas, B. Z., Bergamini F. R. G., Cuin A., Corbi P. P., Synthesis and crystal structure of a palladium (II) complex with the amino acid L-citrulline, 30 (2015) 7156. https://doi.org/10.1017/S0885715615000652.

  45. Patel, M. N., Dosi, P. A., Bhatt B. S., Square planar palladium (II) complexes of bipyridines: synthesis, characterization, and biological studies, 8972 (2012). https://doi.org/10.1080/00958972.2012.727207.

  46. Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248–254. https://doi.org/10.1016/0003-2697(76)90527-3.

    Article  CAS  PubMed  Google Scholar 

  47. Nakamura, Y., Gindhart, T. D., Winterstein, D., Tomita, I., Seed, J. L., & Colburn, N. H. (1988). Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cells. Carcinogenesis., 9, 203–207. https://doi.org/10.1093/carcin/9.2.203.

    Article  CAS  PubMed  Google Scholar 

  48. Beers, R. F., & Sizer, I. W. (1951). A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. Journal of Biological Chemistry, 24, 113–140.

    Google Scholar 

  49. Wendel, A. (1981). Glutathione peroxidase. Methods Enzymol, 77, 325–333. https://doi.org/10.1016/S0076-6879(81)77046-0.

    Article  CAS  PubMed  Google Scholar 

  50. Moron, M., Depierre, J., & Mannervik, B. (1979). Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochimica et Biophysica Acta, 582, 67–78. https://doi.org/10.1016/0304-4165(79)90289-7.

    Article  CAS  PubMed  Google Scholar 

  51. Altay, A., Tohma, H., Durmaz, L., Taslimi, P., Korkmaz, M., Gulcin, I., & Koksal, E. (2019). Preliminary phytochemical analysis and evaluation of in vitro antioxidant, antiproliferative, antidiabetic, and anticholinergics effects of endemic Gypsophila taxa from Turkey. Journal of Food Biochemistry, 43, 1–11. https://doi.org/10.1111/jfbc.12908.

    Article  CAS  Google Scholar 

  52. Banti, C. N. & Hadjikakou, S. K. (2016). Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in metal complexes and their effect at the cellular level. European Journal of Inorganic Chemistry, 3048–3071. https://doi.org/10.1002/ejic.201501480.

  53. Totta, X., Papadopoulou, A. A., Hatzidimitriou, A. G., Papadopoulos, A., & Psomas, G. (2015). Synthesis, structure and biological activity of nickel (II) complexes with mefenamato and nitrogen-donor ligands. Journal of Inorganic Biochemistry, 145, 79–93. https://doi.org/10.1016/j.jinorgbio.2015.01.009.

    Article  CAS  PubMed  Google Scholar 

  54. Giovagnini, L., Marzano, C., Bettio, F., & Fregona, D. (2005). Mixed complexes of Pt(II) and Pd(II) with ethylsarcosinedithiocarbamate and 2-/3-picoline as antitumor agents. Journal of Inorganic Biochemistry, 99, 2139–2150. https://doi.org/10.1016/j.jinorgbio.2005.07.016.

    Article  CAS  PubMed  Google Scholar 

  55. Altay, A., Caglar, S., Caglar, B., & Sahin, Z. S. (2019). Novel silver(I) complexes bearing mefenamic acid and pyridine derivatives: synthesis, chemical characterization and in vitro anticancer evaluation. Inorganica Chimica Acta, 493, 61–71. https://doi.org/10.1016/j.ica.2019.05.008.

    Article  CAS  Google Scholar 

  56. Altay, A., Caglar, S., Caglar, B., & Sahin, O. (2018). Synthesis, structural, thermal elucidation and in vitro anticancer activity of novel silver(I) complexes with non-steroidal anti-inflammatory drugs diclofenac and mefenamic acid including picoline derivatives. Polyhedron., 151, 160–170. https://doi.org/10.1016/j.poly.2018.05.038.

    Article  CAS  Google Scholar 

  57. Gao, X., Li, X., Ho, C. T., Lin, X., Zhang, Y., Li, B., & Chen, Z. (2020). Cocoa tea (Camellia ptilophylla) induces mitochondria-dependent apoptosis in HCT116 cells via ROS generation and PI3K/Akt signaling pathway. Food Res. Int., 129, 108854. https://doi.org/10.1016/j.foodres.2019.108854.

    Article  CAS  PubMed  Google Scholar 

  58. Icsel, C., Yilmaz, V. T., Cevatemre, B., Aygun, M., & Ulukaya, E. (2019). Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines. Journal of Inorganic Biochemistry, 195, 39–50. https://doi.org/10.1016/j.jinorgbio.2019.03.008.

    Article  CAS  PubMed  Google Scholar 

  59. Wang, C., & Youle, R. J. (2009). The role of mitochondria in apoptosis. Annu. Rev. Genet., 43, 95–118. https://doi.org/10.1146/annurev-genet-102108-134850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang, M., Wang, B., Gao, J., Zhang, Y., Xu, W., & Tao, L. (2017). Chemosphere Spinosad induces programmed cell death involves mitochondrial dysfunction and cytochrome C release in Spodoptera frugiperda Sf9 cells. Chemosphere, 169, 155–161. https://doi.org/10.1016/j.chemosphere.2016.11.065.

    Article  CAS  PubMed  Google Scholar 

  61. Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., Wang, K., & Shao, F. (2017). Caspase-3 cleavage of a gasdermin. Nature, 547, 99–103. https://doi.org/10.1038/nature22393.

    Article  CAS  PubMed  Google Scholar 

  62. Wang, Y., Liu, J., Qiu, Y., Jin, M., Chen, X., Fan, G., Wang, R., & Kong, D. (2016). ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells. Oncotarget., 7, 19897–19909. https://doi.org/10.18632/oncotarget.7658.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lin, J., Adam, R. M., Santiestevan, E., & Freeman, M. R. (1999). The Phosphatidylinositol 3′-kinase Pathway Is a Dominant Growth Factor-activated Cell Survival Pathway in LNCaP Human Prostate Carcinoma Cells. Cancer Research, 59, 2891–2897.

    CAS  PubMed  Google Scholar 

  64. Fry, M. J.(2001). Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Research, 3, 304–312.

    Article  CAS  Google Scholar 

  65. Lin, X., Schulz, A., Schulz, A., Overexpression of phosphatidylinositol 3-kinase in human lung cancer, (2001) 293–301. https://doi.org/10.1007/s004230100203.

  66. Nicholson, K. M., & Anderson, N. G. (2002). The protein kinase B/Akt signalling pathway in human malignancy. Cellular Signalling, 14, 381–395. https://doi.org/10.1016/S0898-6568(01)00271-6.

    Article  CAS  PubMed  Google Scholar 

  67. Lin, K., Rong, Y., Chen, D., Zhao, Z., Bo, H., Qiao, A., Hao, X., & Wang, J. (2020). Combination of ruthenium complex and doxorubicin synergistically inhibits cancer cell growth by down-regulating PI3K/AKT signaling pathway. Frontiers in Oncology, 10, 1–13. https://doi.org/10.3389/fonc.2020.00141.

    Article  Google Scholar 

  68. Hua, Z., Dan, L., Qiao, W., Yi, Y., Yao, W., Yun, Z., & Liu, J. (2018). A cyclometalated iridium (III) complex induces apoptosis and autophagy through inhibition of the PI3K / AKT / mTOR pathway. Transition Metal Chemistry, 43, 243–257. https://doi.org/10.1007/s11243-018-0210-z.

    Article  CAS  Google Scholar 

  69. Patel, P., Nadar, V. M., Umapathy, D., Manivannan, S., Venkatesan, R., Antony, V., Arokiyam, J., Pappu, S., Prakash, P. A., Padmanabhan, P., Doxorubicin-conjugated platinum theranostic nanoparticles induce apoptosis via inhibition of a cell survival (PI3K / AKT) signaling pathway in human breast cancer cells, (2020). https://doi.org/10.1021/acsanm.0c02521.

  70. Bhattacharyya, A., Chattopadhyay, R., Mitra, S., Crowe, S. E., Bhattacharyya, A., Chattopadhyay, R., Mitra, S., Crowe, S. E., Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases, (2021) 329–354. https://doi.org/10.1152/physrev.00040.2012.

  71. Zhang, P. & Sadler, P. J. (2017). Redox-active metal complexes for anticancer therapy. European Journal of Inorganic Chemistry, 1541–1548. https://doi.org/10.1002/ejic.201600908.

  72. Barilli, A., Atzeri, C., Bassanetti, I., Ingoglia, F., Asta, V. D., Bussolati, O., Ma, M., Mucchino, C., & Marchio, L. (2014). Oxidative stress induced bycopper and iron complexes with 8‑hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells. American Chemical Society, 11, 1151–1163. https://doi.org/10.1021/mp400592n.

    Article  CAS  Google Scholar 

  73. Mos, M., Sadler, P. J., Enhancement of selectivity of an organometallic anticancer agent by redox modulation, (2015). https://doi.org/10.1021/acs.jmedchem.5b00655.

  74. Sadler, P. J.(2013). Next-generation metal anticancer complexes: multitargeting via redox modulation. American Chemical Society, 52, 12276–12291. https://doi.org/10.1021/ic400835n.

    Article  CAS  Google Scholar 

  75. Al-Khayal, K., Vaali-Mohammed, M. A., Elwatidy, M., Bin Traiki, T., Al-Obeed, O., Azam, M., Khan, Z., Abdulla, M., & Ahmad, R. (2020). A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway. BMC Cancer., 20, 1–17. https://doi.org/10.1186/s12885-020-07165-w.

    Article  CAS  Google Scholar 

  76. Guo, D., Xu, S., Huang, Y., Jiang, H., Yasen, W., Wang, N., Su, Y., Qian, J., Li, J., Zhang, C., & Zhu, X. (2018). Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy. Biomaterials., 177, 67–77. https://doi.org/10.1016/j.biomaterials.2018.05.052.

    Article  CAS  PubMed  Google Scholar 

  77. Hsin, Y. H., Chen, C. F., Huang, S., Shih, T. S., Lai, P. S., & Chueh, P. J. (2008). The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. Toxicology Letters, 179, 130–139. https://doi.org/10.1016/j.toxlet.2008.04.015.

    Article  CAS  PubMed  Google Scholar 

  78. Grimm, E. A., Ellerhorst, J., Tang, C. H., & Ekmekcioglu, S. (2008). Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis. Nitric Oxide, 19, 133–137. https://doi.org/10.1016/j.niox.2008.04.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Korde Choudhari, S., Chaudhary, M., Bagde, S., Gadbail, A. R., & Joshi, V. (2013). Nitric oxide and cancer: a review. World Journal of Surgical Oncology, 11, 1–11. https://doi.org/10.1186/1477-7819-11-118.

    Article  Google Scholar 

  80. Kim, P. K. M., Zamora, R., Petrosko, P., & Billiar, T. R. (2001). The regulatory role of nitric oxide in apoptosis. International Immunopharmacology, 1, 1421–1441. https://doi.org/10.1016/S1567-5769(01)00088-1.

    Article  CAS  PubMed  Google Scholar 

  81. Kohan, R., Collin, A., Guizzardi, S., Tolosa de Talamoni, N., & Picotto, G. (2020). Reactive oxygen species in cancer: a paradox between pro- and anti-tumour activities. Cancer Chemotherapy and Pharmacology, 86, 1–13. https://doi.org/10.1007/s00280-020-04103-2.

    Article  PubMed  Google Scholar 

  82. Güller, P., Budak, H., Şişecioğlu, M., & Çiftci, M. (2020). An in vivo and in vitro comparison of the effects of amoxicillin, gentamicin, and cefazolin sodium antibiotics on the mouse hepatic and renal glutathione reductase enzyme. Journal of Biochemical Molecular Toxicology, 34, 1–10. https://doi.org/10.1002/jbt.22496.

    Article  CAS  Google Scholar 

  83. Altay, A., & Bozoğlu, F. (2017). Salvia fruticosa modulates mRNA expressions and activity levels of xenobiotic metabolizing CYP1A2, CYP2E1, NQO1, GPx, and GST enzymes in human colorectal adenocarcinoma HT-29 cells. Nutrition and Cancer, 69, 892–903. https://doi.org/10.1080/01635581.2017.1339817.

    Article  CAS  PubMed  Google Scholar 

  84. Devereux, M., Shea, D. O., Connor, M. O., Grehan, H., Connor, G., Mccann, M., Rosair, G., Lyng, F., Kellett, A., Walsh, M., Egan, D., & Thati, B. (2007). Synthesis, catalase, superoxide dismutase and antitumour activities of copper (II) carboxylate complexes incorporating benzimidazole 1, 10-phenanthroline and bipyridine ligands:. X-ray Cystal Structures, 26, 4073–4084. https://doi.org/10.1016/j.poly.2007.05.006.

    Article  CAS  Google Scholar 

  85. Wert, K. J., Velez, G., Cross, M. R., Wagner, B. A., Teoh-fitzgerald, M. L., Buettner, G. R., Mcanany, J. J., Olivier, A., Tsang, S. H., Harper, M. M., Domann, F. E., & Bassuk, A. G. (2018). Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface ☆. Free Radical Biology and Medicine, 124, 408–419. https://doi.org/10.1016/j.freeradbiomed.2018.06.024.

    Article  CAS  PubMed  Google Scholar 

  86. Illán-cabeza, N. A., García-garcía, A. R., Martínez-martos, J. M., Ramírez-expósito, M. J., Peña-ruiz, T., & Moreno-carretero, M. N. (2013). Original article A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato- N3) -triphenylphosphine-gold (I): structural studies and in vivo biological effects against experimental glioma. European Journal of Medicinal Chemistry, 64, 260–272. https://doi.org/10.1016/j.ejmech.2013.03.067.

    Article  CAS  PubMed  Google Scholar 

  87. Kovala-demertzi, D., Staninska, M., Garcia-santos, I., Castineiras, A., & Demertzis, M. A. (2011). Synthesis, crystal structures and spectroscopy of meclofenamic acid and its metal complexes with manganese (II), copper (II), zinc (II) and cadmium (II). Antiproliferative and superoxide dismutase activity. Journal of Inorganic Biochemistry, 105, 1187–1195. https://doi.org/10.1016/j.jinorgbio.2011.05.025.

    Article  CAS  PubMed  Google Scholar 

  88. Shahraki, S., Saeidifar, M., & Samareh, H. (2020). Molecular docking and inhibitory effects of a novel cytotoxic agent with bovine liver catalase. Journal of Molecular Structure, 1205, 127590. https://doi.org/10.1016/j.molstruc.2019.127590.

    Article  CAS  Google Scholar 

  89. Signorella, S., Palopoli, C., & Ledesma, G. (2018). Rationally designed mimics of antioxidant manganoenzymes: role of structural features in the quest for catalysts with catalase and superoxide dismutase activity. Coordination Chemistry Reviews, 365, 75–102. https://doi.org/10.1016/j.ccr.2018.03.005.

    Article  CAS  Google Scholar 

  90. Altay, A., Kartal, D. I., Sadi, G., Güray, T., & Yaprak, A. E. (2017). Modulation of mRNA expression and activities of xenobiotic metabolizing enzymes, CYP1A1, CYP1A2, CYP2E1, GPx and GSTP1 by the Salicornia freitagii extract in HT-29 human colon cancer cells. Archives of Biological Sciences, 69, 439–448. https://doi.org/10.2298/ABS160825118A.

    Article  Google Scholar 

  91. Ceylan, H., Budak, H., Fehim, E., & Gonul, N. (2019). Examining the link between dose-dependent dietary iron intake and Alzheimer’s disease through oxidative stress in the rat cortex. Journal of Trace Elements in Medicine and Biology, 56, 198–206. https://doi.org/10.1016/j.jtemb.2019.09.002.

    Article  CAS  PubMed  Google Scholar 

  92. Franco, J. L., Posser, T., Dunkley, P. R., Dickson, P. W., Mattos, J. J., Martins, R., Bainy, A. C. D., Marques, M. R., Dafre, A. L., & Farina, M. (2009). Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase. Free Radical Biology & Medicine, 47, 449–457. https://doi.org/10.1016/j.freeradbiomed.2009.05.013.

    Article  CAS  Google Scholar 

  93. Gross, A. (2016). BCL-2 family proteins as regulators of mitochondria metabolism ☆. Biochimica et Biophysica Acta, 1857, 1243–1246. https://doi.org/10.1016/j.bbabio.2016.01.017.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang, J., Huang, K., Neill, K. L. O., Pang, X., Luo, X., Bax/Bak activation in the absence of Bid, Bim, Puma, and p53, Nature Publishing Group (2016). https://doi.org/10.1038/cddis.2016.167.

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Acknowledgements

This work was financially supported by grants from Erzincan University Scientific Research Projects Coordination Commission (EU-BAP) (Project No: FBA-2016-381).

Author Contributions

A.A., S.C. and M.K. M.K. performed the experiments. A.A. and B.C. designed and analyzed the experiments. A.A. and S.C. wrote the manuscript.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Arts and Sciences, Erzincan Binali Yıldırım University, 24100, Erzincan, Turkey

    Sema Caglar, Ahmet Altay & Bulent Caglar

  2. Department of Biology, Faculty of Arts and Sciences, Erzincan Binali Yıldırım University, 24100, Erzincan, Turkey

    Mehmet Kuzucu

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  1. Sema Caglar
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  2. Ahmet Altay
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  4. Bulent Caglar
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Correspondence to Ahmet Altay.

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Caglar, S., Altay, A., Kuzucu, M. et al. In Vitro Anticancer Activity of Novel Co(II) and Ni(II) Complexes of Non-steroidal Anti-inflammatory Drug Niflumic Acid Against Human Breast Adenocarcinoma MCF-7 Cells. Cell Biochem Biophys 79, 729–746 (2021). https://doi.org/10.1007/s12013-021-00984-z

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