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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

The Effect of a Ferrocene Containing Camphor Sulfonamide DK-164 on Breast Cancer Cell Lines

Author(s): Maria Schröder, Shazie Yusein-Myashkova, Maria Petrova, Georgi Dobrikov, Mariana Kamenova-Nacheva, Jordana Todorova, Evdokia Pasheva and Iva Ugrinova*

Volume 19 , Issue 15 , 2019

Page: [1874 - 1886] Pages: 13

DOI: 10.2174/1871520619666190724094334

Price: $65


Background: Drug resistance is a major cause of cancer treatment failure. Most cancer therapies involve multiple agents, to overcome it. Compounds that exhibit strong anti-tumor effect without damaging normal cells are more and more in the focus of research. Chemotherapeutic drugs, combining different moieties and functional groups in one molecule, can modulate different regulatory pathways in the cell and thus reach the higher efficacy than the agents, which affect only one cellular process.

Methods: We tested the effect of recently synthesized ferrocene-containing camphor sulfonamide DK-164 on two breast cancer and one breast non-cancer cell lines. The cytotoxic effects were evaluated using the standard MTT-dye reduction and clonogenic assays. The apoptotic or autophagic effects were evaluated by Annexin v binding or LC3 puncta formation assays, respectively. Cell cycle arrest was determined using flow cytometry. Western blot and immunofluorescent analyses were used to estimate the localization and cellular distribution of key regulatory factors NFκB and p53.

Results: Compound DK-164 has well pronounced cytotoxicity greater to cancer cells (MDA-MB-231 and MCF-7) compared to non-cancerous (MCF-10A). The IC50 value of the substance caused a cell cycle arrest in G1 phase and induced apoptosis up to 24 hours in both tumor cells, although being more pronounced in MCF-7, a functional p53 cell line. Treatment with IC50 concentration of the compound provoked autophagy in both tumor lines but is better pronounced in the more aggressive cancer line (MDA-MB-231).

Conclusion: The tested compound DK-164 showed promising properties as a potential therapeutic agent.

Keywords: Ferrocene-containing camphor sulfonamide DK-164, breast cancer cells, cytotoxicity, cell cycle arrest, apoptosis, autophagy, NFκB, p53.

Graphical Abstract
Sigurdsson, H.; Baldetorp, B.; Borg, A.; Dalberg, M.; Fernö, M.; Killander, D.; Olsson, H. Indicators of prognosis in node-negative breast cancer. N. Engl. J. Med., 1990, 322(15), 1045-1053.
Richie, R.C.; Swanson, J.O. Breast cancer: A review of the literature. J. Insur. Med., 2003, 35(2), 85-101.
(a) Donegan, W.L. Follow-up after treatment for breast cancer: how much is too much? J. Surg. Oncol., 1995, 59(4), 211-214.
(b) Lourenco, A.P.; Khalil, H.; Sanford, M.; Donegan, L. High-risk lesions at MRI-guided breast biopsy: Frequency and rate of underestimation. AJR Am. J. Roentgenol., 2014, 203(3), 682-686.
(a) Burns, K.A.; Korach, K.S. Estrogen receptors and human disease: An update. Arch. Toxicol., 2012, 86(10), 1491-1504.
(b) Deroo, B.J.; Korach, K.S. Estrogen receptors and human disease. J. Clin. Invest., 2006, 116(3), 561-570.
(a) Cardoso, J.M.S.; Correia, I.; Galvão, A.M.; Marques, F.; Carvalho, M.F.N.N. Synthesis of Ag(I) camphor sulphonylimine complexes and assessment of their cytotoxic properties against cisplatin-resistant A2780cisR and A2780 cell lines. J. Inorg. Biochem., 2017, 166, 55-63.
(b) Pandey, V.; Ansari, M.W.; Tula, S.; Sahoo, R.K.; Bains, G.; Kumar, J.; Tuteja, N.; Shukla, A. Ocimum sanctum leaf extract induces drought stress tolerance in rice. Plant Signal. Behav., 2016, 11(5)e1150400
(c) Moayedi, Y.; Greenberg, S.A.; Jenkins, B.A.; Marshall, K.L.; Dimitrov, L.V.; Nelson, A.M.; Owens, D.M.; Lumpkin, E.A. Camphor white oil induces tumor regression through cytotoxic T cell-dependent mechanisms. Mol. Carcinog., 2018, 58(5), 722-734.
(a) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C.T. Anticancer and antiviral sulfonamides. Curr. Med. Chem., 2003, 10(11), 925-953.
(b) Zhao, C.; Rakesh, K.P.; Ravidar, L.; Fang, W.Y.; Qin, H.L. Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review. Eur. J. Med. Chem., 2019, 162, 679-734.
(c) Abdel-Maksoud, M.S.; El-Gamal, M.I.; Gamal El-Din, M.M.; Oh, C.H. Design, synthesis, in vitro anticancer evaluation, kinase inhibitory effects, and pharmacokinetic profile of new 1,3,4-triarylpyrazole derivatives possessing terminal sulfonamide moiety. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 97-109.
(a) Youle, R.J.; Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol., 2011, 12(1), 9-14.
(b) Eskelinen, E.L. The dual role of autophagy in cancer. Curr. Opin. Pharmacol., 2011, 11(4), 294-300.
Oren, M.; Kotler, E. p53 mutations promote proteasomal activity. Nat. Cell Biol., 2016, 18(8), 833-835.
Stiewe, T.; Haran, T.E. How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance. Drug Resist. Updat. 38, 2018, 27-43.
Chen, J. The Cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med., 2016, 6(3)a026104
Bonizzi, G.; Karin, M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol., 2004, 25(6), 280-288.
(a) Pires, B.R.B.; Silva, R.C.M.C.; Ferreira, G.M.; Abdelhay, E. NF-kappaB: Two Sides of the Same Coin. Genes (Basel), 2018, 9(1)E24
(b) Hoesel, B.; Schmid, J.A. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer, 2013, 12, 86.
Eckstein, N. Platinum resistance in breast and ovarian cancer cell lines. Journal of experimental & clinical cancer research. CR (East Lansing Mich.), 2011, 30, 91.
Kamenova-Nacheva, M.S.; Pasheva, E.; Slavchev, I.; Dimitrov, V.; Momekov, G.; Nikolova, R.; Shivachev, B.; Ugrinova, I.; Dobrikov, G.M. Synthesis of ferrocenylmethylidene and arylidene substituted camphane based compounds as potential anticancer agents. New J. Chem., 2017, 41(17), 9103-9112.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
Guzmán, C.; Bagga, M.; Kaur, A.; Westermarck, J.; Abankwa, D. ColonyArea: An ImageJ plugin to automatically quantify colony formation in clonogenic assays. PLoS One, 2014, 9(3)e92444
Franken, N.A.; Rodermond, H.M.; Stap, J.; Haveman, J.; van Bree, C. Clonogenic assay of cells in vitro. Nat. Protoc., 2006, 1(5), 2315-2319.
Luo, M.; Fu, L. The effect of chemotherapy on programmed cell death 1/programmed cell death 1 ligand axis: Some chemotherapeutical drugs may finally work through immune response. Oncotarget, 2016, 7(20), 29794-29803.
(a) Yun, C.W.; Lee, S.H. The roles of autophagy in cancer. Int. J. Mol. Sci., 2018, 19(11)E3466
(b) Mizushima, N. Autophagy: Process and function. Genes Dev., 2007, 21(22), 2861-2873.
(a) Lorin, S.; Hamaï, A.; Mehrpour, M.; Codogno, P. Autophagy regulation and its role in cancer. Semin. Cancer Biol., 2013, 23(5), 361-379.
(b) White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer, 2012, 12(6), 401-410.
(a) Carlsson, S.R.; Simonsen, A. Membrane dynamics in autophagosome biogenesis. J. Cell Sci., 2015, 128(2), 193-205.
(b) Kabeya, Y.; Mizushima, N.; Ueno, T.; Yamamoto, A.; Kirisako, T.; Noda, T.; Kominami, E.; Ohsumi, Y.; Yoshimori, T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J., 2000, 19(21), 5720-5728.
(a) Tian, B.; Brasier, A.R. Identification of a nuclear factor kappa B-dependent gene network. Recent Prog. Horm. Res., 2003, 58, 95-130.
(b) Albensi, B.C.; Mattson, M.P. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse, 2000, 35(2), 151-159.
(c) Monkkonen, T.; Debnath, J. Inflammatory signaling cascades and autophagy in cancer. Autophagy, 2018, 14(2), 190-198.
Tilborghs, S.; Corthouts, J.; Verhoeven, Y.; Arias, D.; Rolfo, C.; Trinh, X.B.; van Dam, P.A. The role of nuclear factor-kappa B signaling in human cervical cancer. Crit. Rev. Oncol. Hematol., 2017, 120, 141-150.
Ozaki, T.; Nakagawara, A. Role of p53 in cell death and human cancers. Cancers (Basel), 2011, 3(1), 994-1013.
(a) Vousden, K.H.; Prives, C. Blinded by the light: The growing complexity of p53. Cell, 2009, 137(3), 413-431.
(b) Mrakovcic, M.; Fröhlich, L.F. p53-mediated molecular control of autophagy in tumor cells. Biomolecules, 2018, 8(2)E14
Gartel, A.L.; Feliciano, C.; Tyner, A.L. A new method for determining the status of p53 in tumor cell lines of different origin. Oncol. Res., 2003, 13(6-10), 405-408.
Naryzhny, S.N.; Lee, H. Proliferating cell nuclear antigen in the cytoplasm interacts with components of glycolysis and cancer. FEBS Lett., 2010, 584(20), 4292-4298.
Wickberg, A.; Holmberg, L.; Adami, H.O.; Magnuson, A.; Villman, K.; Liljegren, G. Sector resection with or without postoperative radiotherapy for stage I breast cancer: 20-year results of a randomized trial. J. Clin. Oncol., 2014, 32(8), 791-797.
Kartalou, M.; Essigmann, J.M. Mechanisms of resistance to cisplatin. Mutat. Res., 2001, 478(1-2), 23-43.
(a) Ali, S.; Yasin, G.; Zuhra, Z.; Wu, Z.; Butler, I.S.; Badshah, A.; Din, I.U. Ferrocene-based bioactive bimetallic thiourea complexes: Synthesis and spectroscopic studies. Bioinorg. Chem. Appl., 2015, 2015386587
(b) Asghar, F.; Fatima, S.; Rana, S.; Badshah, A.; Butler, I.S.; Tahir, M.N. Synthesis, spectroscopic investigation, and DFT study of N,N′-disubstituted ferrocene-based thiourea complexes as potent anticancer agents. Dalton Trans., 2018, 47(6), 1868-1878.
Top, S.; Tang, J.; Vessieres, A.; Carrez, D.; Provot, C.; Jaouen, G. Ferrocenyl hydroxytamoxifen: A prototype for a new range of oestradiol receptor site-directed cytotoxics. Chem. Commun. (Camb.), 1996, 8, 955-956.
(a) Osella, D.; Ferrali, M.; Zanello, P.; Laschi, F.; Fontani, M.; Nervi, C.; Cavigiolio, G. On the mechanism of the antitumor activity of ferrocenium derivatives. Inorg. Chim. Acta, 2000, 306(1), 42-48.
(b) Asghar, F.; Fatima, S.; Rana, S.; Badshah, A.; Butler, I.S.; Tahir, M.N. Synthesis, spectroscopic investigation, and DFT study of N,N′-disubstituted ferrocene-based thiourea complexes as potent anticancer agents. Dalton Trans., 2018, 47(6), 1868-1878.
Pigeon, P.; Top, S.; Vessieres, A.; Huche, M.; Gormen, M.; El Arbi, M.; Plamont, M.A.; McGlinchey, M.J.; Jaouen, G. A new series of ferrocifen derivatives, bearing two aminoalkyl chains, with strong antiproliferative effects on breast cancer cells. New J. Chem., 2011, 35(10), 2212-2218.
(a) Singh, A.; Lumb, I.; Mehra, V.; Kumar, V. Ferrocene-appended pharmacophores: An exciting approach for modulating the biological potential of organic scaffolds. Dalton Trans., 2019, 48(9), 2840-2860.
(b) Pérez, W.I.; Soto, Y.; Ortíz, C.; Matta, J.; Meléndez, E. Ferrocenes as potential chemotherapeutic drugs: synthesis, cytotoxic activity, reactive oxygen species production and micronucleus assay. Bioorg. Med. Chem., 2015, 23(3), 471-479.
Agus, H.H.; Sengoz, C.O.; Yilmaz, S. Oxidative stress-mediated apoptotic cell death induced by camphor in sod1-deficient Schizosaccharomyces pombe. Toxicol. Res. (Camb.), 2018, 8(2), 216-226.
El-Sayed, N.S.; El-Bendary, E.R.; El-Ashry, S.M.; El-Kerdawy, M.M. Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines. Eur. J. Med. Chem., 2011, 46(9), 3714-3720.
(a) Giuliani, C.; Bucci, I.; Napolitano, G. The role of the transcription factor nuclear factor-kappa B in thyroid autoimmunity and cancer. Front. Endocrinol. (Lausanne), 2018, 9, 471.
(b) Escárcega, R.O.; Fuentes-Alexandro, S.; García-Carrasco, M.; Gatica, A.; Zamora, A. The transcription factor nuclear factor-kappa B and cancer. Clin. Oncol. (R. Coll. Radiol.), 2007, 19(2), 154-161.
Liu, F.; Bardhan, K.; Yang, D.; Thangaraju, M.; Ganapathy, V.; Waller, J.L.; Liles, G.B.; Lee, J.R.; Liu, K. NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. J. Biol. Chem., 2012, 287(30), 25530-25540.
Campbell, K.J.; Rocha, S.; Perkins, N.D. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol. Cell, 2004, 13(6), 853-865.
Kaltschmidt, B.; Kaltschmidt, C.; Hofmann, T.G.; Hehner, S.P.; Dröge, W.; Schmitz, M.L. The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus. Eur. J. Biochem., 2000, 267(12), 3828-3835.
Ashikawa, K.; Shishodia, S.; Fokt, I.; Priebe, W.; Aggarwal, B.B. Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues. Biochem. Pharmacol., 2004, 67(2), 353-364.
Nakanishi, C.; Toi, M. Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer, 2005, 5(4), 297-309.
Rai, A.; Kapoor, S.; Singh, S.; Chatterji, B.P.; Panda, D. Transcription factor NF-κB associates with microtubules and stimulates apoptosis in response to suppression of microtubule dynamics in MCF-7 cells. Biochem. Pharmacol., 2015, 93(3), 277-289.
(a) Georges, S.A.; Biery, M.C.; Kim, S.Y.; Schelter, J.M.; Guo, J.; Chang, A.N.; Jackson, A.L.; Carleton, M.O.; Linsley, P.S.; Cleary, M.A.; Chau, B.N. Coordinated regulation of cell cycle transcripts by p53-inducible microRNAs, miR-192 and miR-215. Cancer Res., 2008, 68(24), 10105-10112.
(b) Chen, J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med., 2016, 6(3)a026104
(c) Pietsch, E.C.; Sykes, S.M.; McMahon, S.B.; Murphy, M.E. The p53 family and programmed cell death. Oncogene, 2008, 27(50), 6507-6521.

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