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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

The Effect of a Newly Synthesized Ferrocene Derivative against MCF-7 Breast Cancer Cells and Spheroid Stem Cells through ROS Production and Inhibition of JAK2/STAT3 Signaling Pathway

Author(s): Mitra Nourbakhsh, Shabnam Farzaneh, Adeleh Taghikhani, Afshin Zarghi* and Shokoofe Noori*

Volume 20, Issue 7, 2020

Page: [875 - 886] Pages: 12

DOI: 10.2174/1871520620666200101151743

Price: $65

Abstract

Background: Breast Cancer Stem Cells (BCSCs) possess the ability of self-renewal and cellular heterogeneity, and therefore, play a key role in the initiation, propagation and clinical outcome of breast cancer. It has been shown that ferrocene complexes have remarkable potential as anticancer drugs.

Objective: The present study was conducted to investigate the effects of a novel ferrocene complex, 1- ferrocenyl-3-(4-methylsulfonylphenyl)propen-1-one (FMSP) on MCF-7 breast cancer cell line and its derived mammospheres with cancer stem cell properties.

Methods: Mammospheres were developed from MCF-7 cells and validated by the evaluation of CD44 and CD24 cell surface markers by flow cytometry as well as of the expression of genes that are associated with stem cell properties by real-time PCR. Cells viability was assessed by a soluble tetrazolium salt (MTS) after the treatment of cells with various concentrations of FMSP. Apoptosis was evaluated by flow cytometry analysis of annexin V and PI labeling of cells. Reactive Oxygen Species (ROS) production was measured using a cellpermeable, oxidant-sensitive fluorescence probe (carboxy-H2DCFDA). The involvement of the JAK2/STAT3 pathway was also investigated by western blotting.

Results: FMSP could successfully prevent mammosphere formation from differentiated MCF-7 cells and significantly down-regulated the expression of genes involved in the production of the stem cell properties including Wnt1, Notch1, β -catenin, SOX2, CXCR4 and ALDH1A1. FMSP decreased cell viability in both MCF-7 cells and spheroid cells, although MCF-10A cells were unaffected by this compound. Apoptosis was also dramatically induced by FMSP, via ROS production but independent of CD95 activation. Phosphorylation levels of JAK2 and STAT3 were also found to be significantly attenuated even in the presence of IL-6, the putative activator of the JAK/STAT pathway.

Conclusion: FMSP can effectively target BCSCs via ROS production and modulation of major signaling pathways that contribute to the stemness of breast cancer cells, and therefore, might be considered a promising anticancer agent after in vivo studies.

Keywords: Breast cancer, stem cells, ferrocene, apoptosis, reactive oxygen species, JAK2, STAT3.

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[1]
Schrecker, A.W.; Hartwell, J.L. Communications-components of podophyllin. XX. The absolute configuration of podophyllotoxin and related lignans. J. Org. Chem., 1956, 21, 381-382.
[http://dx.doi.org/10.1021/jo01109a617]
[2]
MacRae, W.D.; Hudson, J.B.; Towers, G.H.N. The antiviral action of lignans. Planta Med., 1989, 55(6), 531-535.
[http://dx.doi.org/10.1055/s-2006-962087] [PMID: 2559420]
[3]
Lars, B.; Börje, R. Podophyllotoxin derivatives: drug discovery and development. Drug Discov. Today, 1996, 1, 343-351.
[http://dx.doi.org/10.1016/1359-6446(96)10028-3]
[4]
Pitts, S.L.; Jablonksy, M.J.; Duca, M.; Dauzonne, D.; Monneret, C.; Arimondo, P.B.; Anklin, C.; Graves, D.E.; Osheroff, N. Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme--drug--DNA complex. Biochemistry, 2011, 50(22), 5058-5066.
[http://dx.doi.org/10.1021/bi200531q] [PMID: 21548574]
[5]
Passarella, D.; Giardini, A.; Peretto, B.; Fontana, G.; Sacchetti, A.; Silvani, A.; Ronchi, C.; Cappelletti, G.; Cartelli, D.; Borlak, J.; Danieli, B. Inhibitors of tubulin polymerization: synthesis and biological evaluation of hybrids of vindoline, anhydrovinblastine and vinorelbine with thiocolchicine, podophyllotoxin and baccatin III. Bioorg. Med. Chem., 2008, 16(11), 6269-6285.
[http://dx.doi.org/10.1016/j.bmc.2008.04.025] [PMID: 18468444]
[6]
Lee, K.H.; Beers, S.A.; Mori, M.; Wang, Z.Q.; Kuo, Y.H.; Li, L.; Liu, S.Y.; Chang, J.Y.; Han, F.S.; Cheng, Y.C. Antitumor agents. 111. New 4-hydroxylated and 4-halogenated anilino derivatives of 4′-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J. Med. Chem., 1990, 33(5), 1364-1368.
[http://dx.doi.org/10.1021/jm00167a013] [PMID: 2158562]
[7]
Wang, Z.Q.; Kuo, Y.H.; Schnur, D.; Bowen, J.P.; Liu, S.Y.; Han, F.S.; Chang, J.Y.; Cheng, Y.C.; Lee, K.H. Antitumor agents. 113. New 4 beta-arylamino derivatives of 4′-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II. J. Med. Chem., 1990, 33(9), 2660-2666.
[http://dx.doi.org/10.1021/jm00171a050] [PMID: 2167985]
[8]
Baldwin, E.L.; Osheroff, N. Etoposide, topoisomerase II and cancer. Curr. Med. Chem. Anticancer Agents, 2005, 5(4), 363-372.
[http://dx.doi.org/10.2174/1568011054222364] [PMID: 16101488]
[9]
Stähelin, H.; von Wartburg, A. From podophyllotoxin glucoside to etoposide. Prog. Drug Res., 1989, 33, 169-266.
[PMID: 2687938]
[10]
You, Y. Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. Curr. Pharm. Des., 2005, 11(13), 1695-1717.
[http://dx.doi.org/10.2174/1381612053764724] [PMID: 15892669]
[11]
Kamal, A.; Kumar, B.A.; Suresh, P.; Juvekar, A.; Zingde, S. Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents. Bioorg. Med. Chem., 2011, 19(9), 2975-2979.
[http://dx.doi.org/10.1016/j.bmc.2011.03.030] [PMID: 21489802]
[12]
Kamal, A.; Kumar, B.A.; Suresh, P.; Shankaraiah, N.; Kumar, M.S. An efficient one-pot synthesis of benzothiazolo-4β-anilino-podophyllotoxin congeners: DNA topoisomerase-II inhibition and anticancer activity. Bioorg. Med. Chem. Lett., 2011, 21(1), 350-353.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.002] [PMID: 21144748]
[13]
Yang, H.; Hendricks, R.T.; Arora, N.; Nitzan, D.; Yee, C.; Lucas, M.C.; Yang, Y.; Fung, A.; Rajyaguru, S.; Harris, S.F.; Leveque, V.J.P.; Hang, J.Q.; Pogam, S.L.; Reuter, D.; Tavares, G.A. Cyclic amide bioisosterism: strategic application to the design and synthesis of HCV NS5B polymerase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(15), 4614-4619.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.008] [PMID: 20584604]
[14]
VanVliet, D.S.; Tachibana, Y.; Bastow, K.F.; Huang, E.S.; Lee, K.H. Antitumor agents. 207. Design, synthesis, and biological testing of 4beta-anilino-2-fluoro-4′-demethylpodophyllotoxin analogues as cytotoxic and antiviral agents. J. Med. Chem., 2001, 44(9), 1422-1428.
[http://dx.doi.org/10.1021/jm000377f] [PMID: 11311065]
[15]
Wang, H.; Tang, L.; Tang, Y.; Yuan, Z. SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position. Bioorg. Med. Chem., 2014, 22(21), 6183-6192.
[http://dx.doi.org/10.1016/j.bmc.2014.08.025] [PMID: 25282651]
[16]
Wang, H. Podophyllum derivatives containing fluorine atom in the 3-position of 2-aminopyridine improved the antitumor activity by inducing P53-dependent apoptosis. Med. Chem. Res., 2017, 26, 1279-1290.
[http://dx.doi.org/10.1007/s00044-017-1841-x]
[17]
World Health Organization, I.A.f.R.o.C. Estimated cancer incidence,mortality and prevalence worldwide in,. 2012.http://www.globocan.iarc.fr/Pages/fact_sheets_population.aspx
[18]
Kensler, T.W.; Qian, G.S.; Chen, J.G.; Groopman, J.D. Translational strategies for cancer prevention in liver. Nat. Rev. Cancer, 2003, 3(5), 321-329.
[http://dx.doi.org/10.1038/nrc1076] [PMID: 12724730]
[19]
Vogelstein, B.; Kinzler, K.W. Cancer genes and the pathways they control. Nat. Med., 2004, 10(8), 789-799.
[http://dx.doi.org/10.1038/nm1087] [PMID: 15286780]
[20]
Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 2002, 3(6), 415-428.
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769]
[21]
Ozen, C.; Yildiz, G.; Dagcan, A.T.; Cevik, D.; Ors, A.; Keles, U.; Topel, H.; Ozturk, M. Genetics and epigenetics of liver cancer. N. Biotechnol., 2013, 30(4), 381-384.
[http://dx.doi.org/10.1016/j.nbt.2013.01.007] [PMID: 23392071]
[22]
Gouas, D.; Shi, H.; Hainaut, P. The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy. Cancer Lett., 2009, 286(1), 29-37.
[http://dx.doi.org/10.1016/j.canlet.2009.02.057] [PMID: 19376640]
[23]
Szymańska, K.; Hainaut, P. TP53 and mutations in human cancer. Acta Biochim. Pol., 2003, 50(1), 231-238.
[http://dx.doi.org/10.18388/abp.2003_3731] [PMID: 12673364]
[24]
Szymańska, K.; Lesi, O.A.; Kirk, G.D.; Sam, O.; Taniere, P.; Scoazec, J.Y.; Mendy, M.; Friesen, M.D.; Whittle, H.; Montesano, R.; Hainaut, P. Ser-249TP53 mutation in tumour and plasma DNA of hepatocellular carcinoma patients from a high incidence area in the Gambia, West Africa. Int. J. Cancer, 2004, 110(3), 374-379.
[http://dx.doi.org/10.1002/ijc.20103] [PMID: 15095302]
[25]
Liao, P.; Zeng, S.X.; Zhou, X.; Chen, T.; Zhou, F.; Cao, B.; Jung, J.H.; Del Sal, G.; Luo, S.; Lu, H. Mutant p53 gains its function via c-Myc activation upon CDK4 phosphorylation at serine 249 and consequent PIN1 binding. Mol. Cell, 2017, 68(6), 1134-1146.e6.
[http://dx.doi.org/10.1016/j.molcel.2017.11.006] [PMID: 29225033]
[26]
Wang, H.; Liao, P.; Zeng, S.X.; Lu, H. It takes a team: a gain-of-function story of p53-R249S. J. Mol. Cell Biol., 2019, 11(4), 277-283.
[http://dx.doi.org/10.1093/jmcb/mjy086] [PMID: 30608603]
[27]
Wang, H.; Feng, J.; Zhou, T.; Wei, L.; Zhou, J. Involvement of RPL11 in the enhancement of P53 stability by a podophyllum derivative, a topoisomerase II inhibitor. Cell Biol. Int., 2018, 42(1), 121-129.
[http://dx.doi.org/10.1002/cbin.10877] [PMID: 28949066]
[28]
Wang, H.; Feng, J.; Zhou, T.; Wei, L.; Zhou, J. P-3F, a microtubule polymerization inhibitor enhances P53 stability through the change in localization of RPS27a. Int. J. Biochem. Cell Biol., 2017, 92, 53-62.
[http://dx.doi.org/10.1016/j.biocel.2017.09.010] [PMID: 28928040]
[29]
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.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[30]
Bouchard, C.; Staller, P.; Eilers, M. Control of cell proliferation by Myc. Trends Cell Biol., 1998, 8(5), 202-206.
[http://dx.doi.org/10.1016/S0962-8924(98)01251-3] [PMID: 9695840]
[31]
Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126(4), 663-676.
[http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]
[32]
Gordan, J.D.; Thompson, C.B.; Simon, M.C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell, 2007, 12(2), 108-113.
[http://dx.doi.org/10.1016/j.ccr.2007.07.006] [PMID: 17692803]
[33]
Kim, J.; Woo, A.J.; Chu, J.; Snow, J.W.; Fujiwara, Y.; Kim, C.G.; Cantor, A.B.; Orkin, S.H. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell, 2010, 143(2), 313-324.
[http://dx.doi.org/10.1016/j.cell.2010.09.010] [PMID: 20946988]
[34]
Grandori, C.; Gomez-Roman, N.; Felton-Edkins, Z.A.; Ngouenet, C.; Galloway, D.A.; Eisenman, R.N.; White, R.J. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat. Cell Biol., 2005, 7(3), 311-318.
[http://dx.doi.org/10.1038/ncb1224] [PMID: 15723054]
[35]
Dang, C.V. MYC on the path to cancer. Cell, 2012, 149(1), 22-35.
[http://dx.doi.org/10.1016/j.cell.2012.03.003] [PMID: 22464321]
[36]
Chen, B.J.; Wu, Y.L.; Tanaka, Y.; Zhang, W. Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. Int. J. Biol. Sci., 2014, 10(10), 1084-1096.
[http://dx.doi.org/10.7150/ijbs.10190] [PMID: 25332683]
[37]
Rogakou, E.P.; Pilch, D.R.; Orr, A.H.; Ivanova, V.S.; Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem., 1998, 273(10), 5858-5868.
[http://dx.doi.org/10.1074/jbc.273.10.5858] [PMID: 9488723]
[38]
Hainaut, P.; Soussi, T.; Shomer, B.; Hollstein, M.; Greenblatt, M.; Hovig, E.; Harris, C.C.; Montesano, R. Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res., 1997, 25(1), 151-157.
[http://dx.doi.org/10.1093/nar/25.1.151] [PMID: 9016527]
[39]
Finlay, C.A.; Hinds, P.W.; Levine, A.J. The p53 proto-oncogene can act as a suppressor of transformation. Cell, 1989, 57(7), 1083-1093.
[http://dx.doi.org/10.1016/0092-8674(89)90045-7] [PMID: 2525423]
[40]
Baker, S.J.; Markowitz, S.; Fearon, E.R.; Willson, J.K.; Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science, 1990, 249(4971), 912-915.
[http://dx.doi.org/10.1126/science.2144057] [PMID: 2144057]
[41]
Vousden, K.H.; Lu, X. Live or let die: the cell’s response to p53. Nat. Rev. Cancer, 2002, 2(8), 594-604.
[http://dx.doi.org/10.1038/nrc864] [PMID: 12154352]
[42]
Harms, K.; Nozell, S.; Chen, X. The common and distinct target genes of the p53 family transcription factors. Cell. Mol. Life Sci., 2004, 61(7-8), 822-842.
[http://dx.doi.org/10.1007/s00018-003-3304-4] [PMID: 15095006]
[43]
Zheng, L.; Suzuki, H.; Nakajo, Y.; Nakano, A.; Kato, M. Regulation of c-MYC transcriptional activity by transforming growth factor-beta 1-stimulated clone 22. Cancer Sci., 2018, 109(2), 395-402.
[http://dx.doi.org/10.1111/cas.13466] [PMID: 29224245]
[44]
Liu, Y.Q.; Yang, L.; Tian, X. Podophyllotoxin: Current perspectives. Curr. Bioact. Compd., 2007, 3, 37-66.
[http://dx.doi.org/10.2174/157340707780126499]
[45]
Bhat, B.A.; Reddy, P.B.; Agrawal, S.K.; Saxena, A.K.; Kumar, H.M.; Qazi, G.N. Studies on novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl] podophyllotoxins as potential anticancer agents. Eur. J. Med. Chem., 2008, 43(10), 2067-2072.
[http://dx.doi.org/10.1016/j.ejmech.2007.09.015] [PMID: 17988764]
[46]
Reddy, D.M.; Srinivas, J.; Chashoo, G.; Saxena, A.K.; Sampath Kumar, H.M. 4β-[(4-Alkyl)-1,2,3-triazol-1-yl] podophyllotoxins as anticancer compounds: design, synthesis and biological evaluation. Eur. J. Med. Chem., 2011, 46(6), 1983-1991.
[http://dx.doi.org/10.1016/j.ejmech.2011.02.016] [PMID: 21477899]
[47]
Kamal, A.; Kumar, B.A.; Arifuddinc, M. A one-pot, efficient and facile synthesis of 4β-arylaminopodophyllotoxins: Synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors. Tetrahedron Lett., 2003, 44, 8457-8459.
[http://dx.doi.org/10.1016/j.tetlet.2003.09.110]
[48]
Chang, H.; Shyu, K.G.; Lee, C.C.; Tsai, S.C.; Wang, B.W.; Hsien Lee, Y.; Lin, S. GL331 inhibits HIF-1alpha expression in a lung cancer model. Biochem. Biophys. Res. Commun., 2003, 302(1), 95-100.
[http://dx.doi.org/10.1016/S0006-291X(03)00111-6] [PMID: 12593853]
[49]
Kamal, A.; Lakshnai Gayatri, N. An efficient method for 4β-anilino-4′-demethylepipodophylloto- xins: Synthesis of NPF and W-68. Tetrahedron Lett., 1996, 37, 3359-3362.
[http://dx.doi.org/10.1016/0040-4039(96)00546-1]
[50]
Daley, L.; Meresse, P.; Bertounesque, E.; Monneret, C. A one-pot, efficient synthesis of the potent cytotoxic podophyllotoxin derivative NPF. Tetrahedron Lett., 1997, 38, 2673-2676.
[http://dx.doi.org/10.1016/S0040-4039(97)00450-4]
[51]
Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell, 2017, 169(7), 1327-1341.e23.
[http://dx.doi.org/10.1016/j.cell.2017.05.046] [PMID: 28622513]
[52]
Aghemo, A.; Colombo, M. Hepatocellular carcinoma in chronic hepatitis C: from bench to bedside. Semin. Immunopathol., 2013, 35(1), 111-120.
[http://dx.doi.org/10.1007/s00281-012-0330-z] [PMID: 23010890]
[53]
Sangiovanni, A.; Del Ninno, E.; Fasani, P.; De Fazio, C.; Ronchi, G.; Romeo, R.; Morabito, A.; De Franchis, R.; Colombo, M. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology, 2004, 126(4), 1005-1014.
[http://dx.doi.org/10.1053/j.gastro.2003.12.049] [PMID: 15057740]
[54]
Cheng, P.; Cheng, Y.; Su, M.X.; Li, D.; Zhao, G.Z.; Gao, H.; Li, Y.; Zhu, J.Y.; Li, H.; Zhang, T. Bicluster and pathway enrichment analysis of HCV-induced cirrhosis and hepatocellular carcinoma. Asian Pac. J. Cancer Prev., 2012, 13(8), 3741-3745.
[http://dx.doi.org/10.7314/APJCP.2012.13.8.3741] [PMID: 23098464]
[55]
Villar, S.; Ortiz-Cuaran, S.; Abedi-Ardekani, B.; Gouas, D.; Nogueira da Costa, A.; Plymoth, A.; Khuhaprema, T.; Kalalak, A.; Sangrajrang, S.; Friesen, M.D.; Groopman, J.D.; Hainaut, P. Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis. PLoS One, 2012, 7(6), e37707
[http://dx.doi.org/10.1371/journal.pone.0037707] [PMID: 22675488]
[56]
Gouas, D.A.; Villar, S.; Ortiz-Cuaran, S.; Legros, P.; Ferro, G.; Kirk, G.D.; Lesi, O.A.; Mendy, M.; Bah, E.; Friesen, M.D.; Groopman, J.; Chemin, I.; Hainaut, P. TP53 R249S mutation, genetic variations in HBX and risk of hepatocellular carcinoma in The Gambia. Carcinogenesis, 2012, 33(6), 1219-1224.
[http://dx.doi.org/10.1093/carcin/bgs135] [PMID: 22759751]

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