Evaluation cytotoxic activity of Zn(II) phthalocyanine on cancer cells and molecular docking studies

Year 2024, Volume: 6 Issue: 2, 115 - 128, 20.12.2024

Uğur Uzuner , Selcen Çelik Uzuner , İsmail Hakkı Kaya , Çağla Akkol , Meryem Yılmaz , Ece Tuğba Saka

https://doi.org/10.51435/turkjac.1585651

Abstract

In this work, 2(3), 9(10), 16(17), 23(24)-tetrakis-[N-methyl-(1-benzylpiperidin-4-yl)oxy) phthalocyaninato]zinc(II) iodide was synthesized and its agregation behavior was investigated in different solvents and concentrations. After the cytotoxic effect of 2(3), 9(10), 16(17), 23(24)-tetrakis-[N-methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide was tested, the treatment at certain conditions with phthalocyanine was resulted in a significant cell death (around 30%) in AR42J pancreatic cancer cells and Sol8 normal muscle cells but same results were not observed in MDA-MD-231metastatic breast cancer cells.To evaluate mitochondrial membrane potential (MMP), Mitotracker Red staining was performed and the treatment at certain conditions with 2(3), 9(10), 16(17), 23(24)-tetrakis-[N-methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide was resulted in a significant decrease in mitochondrial membrane potential (represented by Δψm) in MDA-MB-231 cells, but the same situation was not observed inother cells. In silicoanalyseswere performed for intracellular target prediction of 2(3), 9(10), 16(17), 23(24)-tetrakis-[N-methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide and we found that it has inhibitory effects on Sigmar1 protein and Adinopection receptors 1-2 with the lowest binding energiesas–13.07kcal/mol, –10.93kcal/moland –9.49 kcal/mol, respectively. Sigmar1 is an integral protein localized in mitochondrial membraneswhile communication between mitochondria and endoplasmic reticulum and Adiponectin receptors are known to be associated with mitochondrial function. These results suggest that 2(3), 9(10), 16(17), 23(24)-tetrakis-[N-methyl-(1-benzylpiperidin-4-yl)oxy)phthalocyaninato]zinc(II) iodide has a cytotoxic potential on cancer cells and inhibited MMP in breast cancer cells only.

Keywords

zinc (II) phthalocyanine, aggregation, water soluble, metastatic breast cancer, mitochondrial membrane potential, molecular docking.

References

• Ertem, B., Yalazan, H., Gungor, O., Sarkı, G., Durmus, M., Saka, E.T., Kantekin, H., Synthesis, structural characterization, and investigation on photophysical and photochemical features of new metallophthalocyanines, J Lumin, 204, 2018, 464–471.
• Saka, E.T., Tekintas, K., Light driven photodegradation of 4-nitrophenol with novel Co and Cu phthalocyanine in aqueous media, J Mol Struct, 1215, 2020, 128189.
• Onsal, G., Improvement of the dielectric and electro-optic properties of phthalocyanine-and quantum dot-doped nematic liquid crystals under UV illumination, J Electron Mater, 51, 2022, 3820–3830.
• Comeau, Z.J., Cranston, R.R., Lamontagne, H.R., Harris, C.S., Shuhendler, A.J., Lessard, B.H., Surface engineering of zinc phthalocyanine organic thin-film transistors results in part-per billion sensitivity towards cannabinoid vapor, Commun Chem, 5, 2022, 178–184.
• Rytel, K., Kedzierski, K., Barszcz, B., Biadasz, A., Majchrzycki, L., Wrobel, D., The influence of zinc phthalocyanine on the formation and properties of multiwalled carbon nanotubes thin films on the air–solid and air–water interface, J Mol Liq, 350, 2022, 118548.
• Ivanova, V., Klyamer, D., Krasnov, P., Kaya, E.N., Kulu, I., Kostakoglu, S.T., Durmus, M., Basova, T., Hybrid materials based on pyrene-substituted metallo phthalocyanines as sensing layers for ammonia detection: Effect of the number of pyrene substituents, Sens Actuators B Chem, 375, 2023, 132843.
• Sukhikh, A., Klyamer, D., Bonegardt, D., Popovetsky, P., Krasnov, P., Basova, T., Tetrafluorosubstituted titanyl phthalocyanines: Structure of single crystals and phase transition in thin films, Dyes and Pigments, 231, 2024, 112391.
• Saka, E.T., Kahriman, N., (E)-4-(4-(3-(2-fluoro-5 (trifluoromethyl)phenyl)acryloyl)phenoxy)Substituted Co(II) and Cu(II) phthalocyanines and their catalytic activities on the oxidation of phenols, J Organomet Chem, 895, 2019, 48-58.
• Saka, E.T., Bıyıklıoglu, Z., Kantekin, H., Microwave-assisted synthesis and characterization of Co(II) phthalocyanine and investigation of its catalytic activity on 4-nitrophenol oxidation, Turk J Chem, 38, 2014, 1166.
• Yalazan, H., Akkol, C., Saka, E.T., Kantekin, H., Investigation of photocatalytic properties of cobalt phthalocyanines on benzyl alcohol photoxidation, Appl Organomet Chem, 37, 2023, e6975.
• Saka, E.T., Yalazan, H., Bıyıklıoglu, Z., Kantekin, H., Tekintas, K., Synthesis, aggregation, photocatalytical and electrochemical properties of axially 1-benzylpiperidin-4-oxy units substituted silicon phthalocyanine, J Mol Struct, 1199, 2020, 126994.
• Ben-Hur, E., Green, M., Prager, A., Kol, R., Rosenthal, I., Phthalocyanine Photosensitization of Mammalian Cells: Biochemical and Ultrastructural Effects, Photochem Photobiol, 4, 1987, 651.
• MacDonald, I.J., Dougherty, T.J., Basic principles of photodynamic therapy, J Porphyrins Phthalocyanines, 5, 2001, 105.
• Ali, H., van Lier, J.E., Metal complexes as photo-and radiosensitizers, Chem Rev, 99, 1999, 2379.
• Bonnett, R., Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy, Chem Soc Rev, 24, 1995, 19.
• Tedesco, A.C., Rotta, J.C.G., Lunardi, C.N., Synthesis, Photophysical and Photochemical Aspects of Phthalocyanines for Photodynamic Therapy, Curr Org Chem, 7, 2003, 187.
• Göl, C., Durmus, M., Investigation of photophysical, photochemical and bovine serum albumin binding properties of novel water-soluble zwitterionic zinc phthalocyanine complexes, Synth Met, 162, 2012, 605.
• Gunsel, A., Yıldırım, A., Taslimi, P., Erden, Y., Taskın Tok, T., Piskin, H., Bilgicli, A.T., Gulcin, I., Yarasir, M. N., Cytotoxicity effects and biochemical investigation of novel tetrakis phthalocyanines bearing 2-thiocytosine moieties with molecular docking studies, Inorg Chem Commun, 138, 2022, 109263.
• Dominguez, D. D., Snow, A.W., Shirk, J.S., Pong, R.G.S., Role of Structural Factors in the Nonlinear Optical Properties of Phthalocyanines and Related Compounds, J Porphyrins Phthalocyanines, 5, 2002, 581.
• Masilela, N., Nyokong, T., The synthesis and photophysical properties of water soluble tetrasulfonated, octacarboxylated and quaternised 2,(3)-tetra-(2 pyridiloxy) Ga phthalocyanines, Dyes Pigments, 84, 2010, 242.
• Wei, S., Zhou, J., Huang, D., Wang, X., Zhang, B., Shen, J., Synthesis and Type I/Type II photosensitizing properties of a novel amphiphilic zinc phthalocyanine, Dyes Pigments, 71, 2006, 61.
• Aggarwal, S., Gabrovsek, L., Langeberg, L.K., Golkowski, M., Ong, S., Smith, F.D., Scott, J.D., Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility, J Biol Chem, 294(9), 2019, 3152.
• Sari, C., Degirmencioglu, I., Celep, F., Synthesis and characterization of novel Schiff base silicon (IV) phthalocyanine complex for photodynamic therapy of breast cancer cell lines, Photodiagnosis Photodyn Ther, 42, 2023, 103504.
• Saka, E.T., Biyiklioglu, Z., Co(II) and Fe(II) phthalocyanines: synthesis, investigation of their catalytic activity towards phenolic compounds and electrochemical behaviour, Appl Organomet Chem, 29, 2015, 392.
• Dilber, G., Durmus, M., Kantekin, H., Investigation of the photophysical and photochemical behavior of substituted zinc phthalocyanines and their water-soluble quaternized derivatives, Turk J Chem, 41, 2017, 917.
• Perrin, D.D., Armarego, W.L.F., Purification of Laboratory Chemicals, 1989, Oxford, PergamonPres.
• Kaya, H.İ., Boguslu, C., Kabak, E., Akkol, C., Saka, E.T., Uzuner, S.C., The effect of silicon phthalocyanine on cell death and mitochondrial membrane potential in pancreatic cancer cells, Turk J Anal Chem, 4(2), 2022, 111.
• Schmidt, J., Kuzyniak, W., Berkholz, J., Steinemann, G., Ogbodu, R., Hoffmann, B., Nouailles, G., Gurek, A.G., Nitzsche, B., Höpfner, M., Novel zinc- and silicon-phthalocyanines as photosensitizers for photodynamic therapy of cholangiocarcinoma, Int J Mol Med, 42(1), 2018, 534.
• Simioni, A.R., Primo, F.L., Tedesco, A.C., Silicon(IV) phthalocyanine-loaded-nanoparticles for application in photodynamic process, J Laser Appl, 24(1), 2012, 012004.
• Nalçaoğlu, A., Sarı, C., Degirmencioglu, I., Celep Eyuboglu, F., Novel piperazine-substituted silicon phthalocyanines exert anti-cancer effects against breast cancer cells, Photodiagnosis Photodyn Ther, 37, 2022, 102734.
• Cakmak, U., Oz-Tuncay, F., Basoglu-Ozdemir, S., Ayazoglu-Demir, E., Demir, I., Colak, A., Celik-Uzuner, S., Erdem, S.S., Yildirim, N., Synthesis of hydrazine containing piperazine or benzimidazole derivatives and their potential as α-amylase inhibitors by molecular docking, inhibition kinetics and in vitro cytotoxicity activity studies, Med Chem Res, 30(10), 2021, 1886.
• Uzuner, S.C., Birinci, E., Tetikoğlu, S., Birinci, C., Kolaylı, S., Distinct Epigenetic Reprogramming, Mitochondrial Patterns, Cellular Morphology, and Cytotoxicity after Bee Venom Treatment, Recent Pat Anticancer Drug Discov, 16(3), 2021, 377.
• Keiser, M.J., Roth, B.L., Armbruster, B.N., Ernsberger, P., Irwin, J.J., Shoichet, B.K., Relating protein pharmacology by ligand chemistry, Nat Biotechnol, 25(2), 2007, 197–206.
• O’Boyle, N.M., Banck, M., James, C.A., Morley, C., Vandermeersch, T., Hutchison, G.R., Open Babel: An open chemical toolbox, J Cheminform, 3(1), 2011, 33.
• Eberhardt, J., Santos-Martins, D., Tillack, A.F., Forli, S., AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings, J Chem Inf Model, 61(8), 2001, 3891.
• Santos-Martins, D., Forli, S., Ramos, M.J., Olson, A.J., AutoDock4Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins, J Chem Inf Model, 54(8), 2014, 2371.
• Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Olson, A.J., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility, J Comput Chem, 30(16), 2009, 2785.
• Durmuş, M., Yaman, H., Göl, C., Ahsen, V., Nyokong, T., Water-soluble quaternized mercaptopyridine-substituted zinc-phthalocyanines: Synthesis, photophysical, photochemical and bovine serum albumin binding properties, Dyes Pigments, 91, 2011, 153.
• Çakir, V., Çakir, D., Pişkin, M., Durmuş, M., Biyiklioglu, Z., New peripherally and non-peripherally tetra-substituted water soluble zinc phthalocyanines: Synthesis, photophysics and photochemistry, J Organomet Chem, 783, 2015, 120-129.
• Uslan, C., Sesalan, B.Ş., Durmuş, M., Synthesis of new water-soluble phthalocyanines and investigation of their photochemical, photophysical and biological properties, J Photochem Photobiol A Chem, 235, 2012, 56-64.
• Saka, E.T., Göl, C., Durmus, M., Kantekin, H., Biyiklioglu, Z., Photophysical, photochemical and aggregation behavior of novel peripherally tetra-substituted phthalocyanine derivatives, J Photochem Photobiol A Chem, 241, 2012, 67-78.
• Edwards, L., Gouterman, M., Porphyrins: XVI. Vapor absorption spectra and redox reactions: Octalkylporphins, J Mol Spectrosc, 35, 1970, 90-109.
• El Khatib, N., Boudjema, B., Maitrot, M., Chermette, H., Porte, L., Electronic structure of zinc phthalocyanine, Can J Chem, 66, 1988, 1087–1095.
• Nyokong, T., Gasyna, Z., Stillman, M.J., Analysis of the Absorption and Magnetic Circular Dichroism Spectra of Zinc Phthalocyanine and the 7-Cation-Radical Species [ZnPc(-1)]+, Inorg Chem, 26, 1987, 1087–1095.
• Bernauer, K., Fallab, S., Helv. Phtalocyanine in wässeriger Lösung I, Helv Chim Acta, 44, 1961, 1287-1292.
• Stillman, M.J., Nyokong, T., Absorption and Magnetic Circular Dichroism Spectral Properties of Phthalocyanines, Editors: C.C. Leznoff, A.B.P. Lever, 1989, New York, VCH.
• Snow, A.W., Phtalocyanine Aggregation, The Porphyrin Handbook, Editors: K.M. Kadish, K.M. Smith, R. Guilard, Academic Press, 2003, Amsterdam, Academic Press.
• L’Her, M., Göktuğ, O., Durmuş, M., Ahsen, V., A water soluble zinc phthalocyanine: physicochemical, electrochemical studies and electropolymerization, Electrochim Acta, 213, 2016, 655-662.
• Castro, K.A.D.F., Prandini, J.A., Biazzotto, J.C., Tome, J.P.C., da Silva, R.S., Lourenço, L.M.O., The Surprisingly Positive Effect of Zinc-Phthalocyanines with High Photodynamic Therapy Efficacy of Melanoma Cancer, Front Chem, 10, 2022, 82716.
• Silva, E.P.O., Santos, E.D., Gonçalves, C.S., Cardoso, M.A.G., Soares, C.P., Beltrame Jr, M., Zinc phthalocyanine-conjugated with bovine serum albumin mediated photodynamic therapy of human larynx carcinoma, Laser Phys, 26, 2016, 105601.
• Lara, P., Huis in ‘t Veld, R.V., Jorquera-Cordero, C., Chan, A.B., Ossendorp, F., Cruz, L.J., Zinc-Phthalocyanine-Loaded Extracellular Vesicles Increase Efficacy and Selectivity of Photodynamic Therapy in Co-Culture and Preclinical Models of Colon Cancer, Pharmaceutics, 13, 2021, 1547.
• Toubia, I., Nguyen, C., Diring, S., Pays, M., Mattana, E., Arnoux, P., Frochot, C., Bobo, M.G., Kobeissi, M., Odobel, F., Study of Cytotoxic and Photodynamic Activities of Dyads Composed of a Zinc Phthalocyanine Appended to an Organotin, Pharmaceuticals, 14, 2021, 413.
• Rajabi, N., Mohammadnejad, F., Doustvandi, M.A., Shadbad, M.A., Amini, M., Tajalli, H., Mokhtarzadeh, A., Baghbani, E., Silvestris, N., Baradaran, B., Photodynamic therapy with zinc phthalocyanine enhances the anti-cancer effect of tamoxifen in breast cancer cell line: Promising combination treatment against triple-negative breast cancer?, Photodiagnosis Photodyn Ther, 41, 2023, 103212.
• Ge, Y., Weng, X., Tian, T., Ding, F., Huang, R., Yuan, L., Wu, J., Wang, T., Guo, P., Zhou, X., A mitochondria-targeted zinc(ii) phthalocyanine for photodynamic therapy, RSC Adv, 3, 2013, 12839.
• Shao, J., Xue, J., Dai, Y., Liu, H., Chen, N., Jia, L., Huang, J., Inhibition of human hepatocellular carcinoma HepG2 by phthalocyanine photosensitizer PHOTOCYANINE: ROS production, apoptosis, cell cycle arrest, Eur J Cancer, 48, 2012, 2086.
• Perrin Tamietti, B.F., Machado, A.H.A., Maftoum Costa, M., da Silva, N.S., Tedesco, A.C., Pacheco Soares, C., Analysis of Mitochondrial Activity Related to Cell Death after PDT with AlPCS4, Photomed Laser Surg, 25, 2007, 2040.
• Okada-Iwabu, M., Iwabu, M., Kadowaki, T., Drug development research for novel adiponectin receptor-targeted antidiabetic drugs contributing to healthy longevity, Diabetol Int, 10, 2019, 237.
• Pepin, M.E., Koentges, C., Pfeil, K., Gollmer, J., Kersting, S., Wiese, S., Hoffmann, M.M., Odening, K.E., Mühlen, C., von zur Diehl, P., Stachon, P., Wolf, D., Wende, A.R., Bode, C., Zirlik, A., Bugger, H., Front Endocrinol, 10, 2019, 872.
• Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato, K., Nakagawa, T., Funata, M., Yamaguchi, M., Namiki, S., Nakayama, R., Tabata, M., Ogata, H., Kubota, N., Takamoto, I., Hayashi, Y.K., Yamauchi, N., Waki, H., Fukayama, M., Nishino, I., Tokuyama, K., Kadowaki, T., Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1, Nature, 464, 2010, 1313–1319.
• Xu, H., Zhao, Q., Song, N., Yan, Z., Lin, R., Wu, S., Jiang, L., Hong, S., Xie, J., Zhou, H., Wang, R., Jiang, X., AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis, Nat Commun, 11, 2020, 5807.
• Abdullah, C.S., Aishwarya, R., Alam, S., Remex, N.S., Morshed, M., Nitu, S., Miriyala, S., Panchatcharam, M., Hartman, B., King, J., Nobel Bhuiyan, M.A., Traylor, J., Kevil, C.G., Orr, A.W., Bhuiyan, S.M., The molecular role of Sigmar1 in regulating mitochondrial function through mitochondrial localization in cardiomyocytes, Mitochondrion, 62, 2022, 159-175.
• Aishwarya, R., Abdullah, C.S., Morshed, M., Remex, N.S., Bhuiyan, S.M., Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology, Front Physiol, 12, 2021, 705575.
• Hayashi, T., Su, T.P., Sigma-1 Receptor Chaperones at the ER-Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival, Cell, 131, 2007, 596-610.
• Simony-Lafontaine, J., Esslimani, M., Bribes, E., Gourgou, S., Lequeux, N., Lavail, R., Grenier, J., Kramar, A., Casellas, P., Immunocytochemical assessment of sigma-1 receptor and human sterol isomerase in breast cancer and their relationship with a series of prognostic factors, Br J Cancer, 82, 2000, 1958–1966.
• Magouliotis, D., Tasiopoulou, V., Dimas, K., Sakellaridis, N., Zacharoulis, D., Gene expression profile of sigma-1 (s1R) and sigma-2 (s2R) receptors in pancreatic cancer, HPB, 20, 2018, S564.
• Mahalingam, S.M., Ordaz, J.D., Low, P.S., Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy, ACS Omega, 3, 2018, 6066–6074.
• Thomas, A.P., Palanikumar, L., Jeena, M.T., Kim, K., Ryu, J.H., Cancer-mitochondria-targeted photodynamic therapy with supramolecular assembly of HA and a water soluble NIR cyanine dye, Chem Sci, 12, 2017, 8351-8356.
• Gottlieb, E., Armour, S.M., Harris, M.H., Thompson, C.B., Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis, Cell Death Differ, 10, 2003, 709–717.
• Ly, J.D., Grubb, D.R., Lawen, A., The mitochondrial membrane potential (Δψm) in apoptosis; an update, Apoptosis, 8, 2003, 115–128.
• Rai, Y., Pathak, R., Kumari, N., Sah, D.K., Pandey, S., Kalra, N., Soni, R., Dwarakanath, B.S., Bhatt, A.N., Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition, Sci Rep, 8, 2018, 1531.