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Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells

  • Estefany Ingrid Medina-Reyes
  • Marco Antonio Mancera-Rodríguez
  • Norma Laura Delgado-Buenrostro
  • Adriana Moreno-Rodríguez
  • Juan Luis Bautista-Martínez
  • Clara Estela Díaz-Velásquez
  • Stefanía Andrea Martínez-Alarcón
  • Hugo Torrens
  • María de los Ángeles Godínez-Rodríguez
  • Luis Ignacio Terrazas-Valdés
  • Yolanda Irasema Chirino
  • Felipe Vaca-PaniaguaEmail author
PRECLINICAL STUDIES
  • 63 Downloads

Summary

Cis-diamminedichloroplatinum(II) (CDDP), known as cisplatin, has been extensively used against breast cancer, which is the most frequent cancer among women, and lung cancer, the leading cancer that causes death worldwide. Novel compounds such as thiazole derivatives have exhibited antiproliferative activity, suggesting they could be useful against cancer treatment. Herein, we synthesized two novel thiosemicarbazones and an aldehyde to combine with CDDP to enhance efficacy against ER-positive breast MCF7 cancer cells, triple-negative/basal-B mammary carcinoma cells (MDA-MB231) and lung adenocarcinoma (A549) human cells. We synthesized 2,3,5,6-tetrafluoro-4-(2-mercaptoetanothiolyl)benzaldehyde (ALD), 5-[(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC1) and 5-[(4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC2) and used them alone or in combination with subtoxic CDDP concentrations to evaluate cytotoxicity, cytoskeleton integrity and mitochondrial function. We found that none of the synthesized compounds improved CDDP activity against MCF7 cell cultures; however, TSC2 was effective in enhancing the cytotoxicity of CDDP against MDA-MB231 and A549 cancer cell cultures. We demonstrated that the cytotoxic effect is related to the TSC2 capacity to induce disruption in the cytoskeleton network and to decrease mitochondrial function.

Keywords

Thiosemicarbazones Cytoskeleton disruption Mitochondrial dysfunction Breast cancer cells Lung cancer cells 

Notes

Funding

This research was supported by Programa de Apoyo a los Profesores de Carrera para Promover Grupos de Investigación (PAPCA, Facultad de Estudios Superiores Iztacala, UNAM; FESI-DIP-PAPCA-2014-36) and the National Council of Science and Technology (CONACyT 268769). Medina-Reyes Estefany Ingrid is a doctoral student from Programa de Doctorado en Ciencias Biomédicas de la Universidad Nacional Autónoma de México (UNAM) and received fellowship 576227 from CONACYT.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

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

Supplementary material

10637_2019_789_MOESM1_ESM.pdf (548 kb)
ESM 1 (PDF 547 kb)
10637_2019_789_MOESM2_ESM.pdf (1.9 mb)
ESM 2 (PDF 1968 kb)

References

  1. 1.
    Rosenberg B, Vancamp L, Krigas T (1965) Inhibition of cell division in escherichia coli by electrolysis products from a platinum electrode. Nature 205:698–699.  https://doi.org/10.1038/205698a0 CrossRefGoogle Scholar
  2. 2.
    Iyer G, Balar AV, Milowsky MI, Bochner BH, Dalbagni G, Donat SM, Herr HW, Huang WC, Taneja SS, Woods M, Ostrovnaya I, al-Ahmadie H, Arcila ME, Riches JC, Meier A, Bourque C, Shady M, Won H, Rose TL, Kim WY, Kania BE, Boyd ME, Cipolla CK, Regazzi AM, Delbeau D, McCoy AS, Vargas HA, Berger MF, Solit DB, Rosenberg JE, Bajorin DF (2018) Multicenter prospective phase II trial of neoadjuvant dose-dense gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer. J Clin Oncol 36:1949–1956.  https://doi.org/10.1200/jco.2017.75.0158 CrossRefGoogle Scholar
  3. 3.
    Park IH, Kong SY, Kwon Y, Kim MK, Sim SH, Joo J, Lee KS (2018) Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer. J Cancer 9:1145–1151.  https://doi.org/10.7150/jca.24035 CrossRefGoogle Scholar
  4. 4.
    Forster M, Hackshaw A, de Pas T, Cobo M, Garrido P, Summers Y, Dingemans AMC, Flynn M, Schnell D, von Wangenheim U, Loembé AB, Kaiser R, Lee SM (2018) A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-lung 3). Lung Cancer 120:27–33.  https://doi.org/10.1016/j.lungcan.2018.03.007 CrossRefGoogle Scholar
  5. 5.
    Li M, Zhai G, Gu X, Sun K (2018) ATF3 and PRAP1 play important roles in cisplatin-induced damages in microvascular endothelial cells. Gene 672:93–105.  https://doi.org/10.1016/j.gene.2018.06.017 CrossRefGoogle Scholar
  6. 6.
    Lin M, Lv D, Zheng Y, Wu M, Xu C, Zhang Q, Wu L (2018) Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther 11:3101–3110.  https://doi.org/10.2147/ott.s163266 CrossRefGoogle Scholar
  7. 7.
    Li Q, Zhang J, Zhou J, Yang B, Liu P, Cao L, Jing L, Liu H (2018) lncRNAs are novel biomarkers for differentiating between cisplatin-resistant and cisplatin-sensitive ovarian cancer. Oncol Lett 15:8363–8370.  https://doi.org/10.3892/ol.2018.8433 Google Scholar
  8. 8.
    Duan S, Yin J, Bai Z, Zhang Z (2018) Effects of taxol resistance gene 1 on the cisplatin response in gastric cancer. Oncol Lett 15:8287–8294.  https://doi.org/10.3892/ol.2018.8390 Google Scholar
  9. 9.
    Akladios FN, Andrew SD, Boog SJ, de Kock C, Haynes RK, Parkinson CJ (2019) The evaluation of metal co-ordinating bis-thiosemicarbazones as potential anti-malarial agents. Med Chem 15:51–58.  https://doi.org/10.2174/1573406414666180525132204 CrossRefGoogle Scholar
  10. 10.
    de Santana TI, Barbosa MO, Gomes P, da Cruz ACN, da Silva TG, Leite ACL (2018) Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur J Med Chem 144:874–886.  https://doi.org/10.1016/j.ejmech.2017.12.040 CrossRefGoogle Scholar
  11. 11.
    Malarz K, Mrozek-Wilczkiewicz A, Serda M, Rejmund M, Polanski J, Musiol R (2018) The role of oxidative stress in activity of anticancer thiosemicarbazones. Oncotarget 9:17689–17710.  https://doi.org/10.18632/oncotarget.24844 CrossRefGoogle Scholar
  12. 12.
    Qi J, Yao Q, Qian K, Tian L, Cheng Z, Yang D, Wang Y (2018) Synthesis, antiproliferative activity and mechanism of gallium(III)-thiosemicarbazone complexes as potential anti-breast cancer agents. Eur J Med Chem 154:91–100.  https://doi.org/10.1016/j.ejmech.2018.05.016 CrossRefGoogle Scholar
  13. 13.
    Sirbu A, Palamarciuc O, Babak MV, Lim JM, Ohui K, Enyedy EA, Shova S, Darvasiova D, Rapta P, Ang WH, Arion VB (2017) Copper(ii) thiosemicarbazone complexes induce marked ROS accumulation and promote nrf2-mediated antioxidant response in highly resistant breast cancer cells. Dalton Trans 46:3833–3847.  https://doi.org/10.1039/c7dt00283a CrossRefGoogle Scholar
  14. 14.
    Rodriguez-Fanjul V, Lopez-Torres E, Mendiola MA, Pizarro AM (2018) Gold(III) bis(thiosemicarbazonate) compounds in breast cancer cells: cytotoxicity and thioredoxin reductase targeting. Eur J Med Chem 148:372–383.  https://doi.org/10.1016/j.ejmech.2018.02.009 CrossRefGoogle Scholar
  15. 15.
    Guo ZL, Richardson DR, Kalinowski DS, Kovacevic Z, Tan-Un KC, Chan GC (2016) The novel thiosemicarbazone, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibits neuroblastoma growth in vitro and in vivo via multiple mechanisms. J Hematol Oncol 9:98.  https://doi.org/10.1186/s13045-016-0330-x CrossRefGoogle Scholar
  16. 16.
    Soares MA, Lessa JA, Mendes IC, da Silva JG, dos Santos RG, Salum LB, Daghestani H, Andricopulo AD, Day BW, Vogt A, Pesquero JL, Rocha WR, Beraldo H (2012) N(4)-phenyl-substituted 2-acetylpyridine thiosemicarbazones: cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action. Bioorg Med Chem 20:3396–3409.  https://doi.org/10.1016/j.bmc.2012.04.027 CrossRefGoogle Scholar
  17. 17.
    Zhang B, Luo H, Xu Q, Lin L, Zhang B (2017) Antitumor activity of a trans-thiosemicarbazone schiff base palladium (II) complex on human gastric adenocarcinoma cells. Oncotarget 8:13620–13631.  https://doi.org/10.18632/oncotarget.14620 Google Scholar
  18. 18.
    Bartolak-Suki E, Imsirovic J, Nishibori Y, Krishnan R, Suki B (2017) Regulation of mitochondrial structure and dynamics by the cytoskeleton and mechanical factors. Int J Mol Sci 18:1812.  https://doi.org/10.3390/ijms18081812 CrossRefGoogle Scholar
  19. 19.
    Bautista JL, Tiburcio J, Torrens H (2005) Synthesis of the new 5-(Fluorobenzenethiolated)-2-furfuraldehyde thiosemicarbazones. Synthesis 2005:899–902.  https://doi.org/10.1055/s-2005-861835 CrossRefGoogle Scholar
  20. 20.
    Venkatachalam TK, Pierens GK, Reutens DC (2014) Synthesis, NMR structural characterization and molecular modeling of substituted thiosemicarbazones and semicarbazones using DFT calculations to prove the syn/anti isomer formation. Magn Reson Chem 52:98–105.  https://doi.org/10.1002/mrc.4041 CrossRefGoogle Scholar
  21. 21.
    Lobana TS, Sánchez A, Casas JS, Castiñeiras A, Sordo J, García-Tasende MS, Vázquez-López EM (1997) Symmetrisation, isomerism and structural studies on novel phenylmercury(II) thiosemicarbazonates: correlation of the energy barrier to rotation of the amino group with the bonding parameters of the thioamide group. J Chem Soc Dalton Trans:4289–4300.  https://doi.org/10.1039/a703726k
  22. 22.
    Mamedov IG, Bayramov MR, Mamedova YV, Maharramov AM (2013) Molecular dynamics of 6-methyl-2-phenyl-2,3-dihydro-4H-chromen-4-one and 6-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-chromen-4-one (flavanone) derivatives in a solution studied by NMR spectroscopy. Magn Reson Chem 51:234–239.  https://doi.org/10.1002/mrc.3933 CrossRefGoogle Scholar
  23. 23.
    Emsley JW, Phillips L, Wray V (1976) Flourine coupling constants. Prog NMR Spectr 10:83–752.  https://doi.org/10.1016/s0079-6565(76)80005-2 CrossRefGoogle Scholar
  24. 24.
    Kunos CA, Ivy SP (2018) Triapine radiochemotherapy in advanced stage cervical cancer. Front Oncol 8:149.  https://doi.org/10.3389/fonc.2018.00149 CrossRefGoogle Scholar
  25. 25.
    Knox JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, Eisenhauer EA (2007) Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada clinical trials group (NCIC IND.161). Investig New Drugs 25:471–477.  https://doi.org/10.1007/s10637-007-9044-9 CrossRefGoogle Scholar
  26. 26.
    Haldys K, Goldeman W, Jewginski M, Wolinska E, Anger N, Rossowska J, Latajka R (2018) Inhibitory properties of aromatic thiosemicarbazones on mushroom tyrosinase: synthesis, kinetic studies, molecular docking and effectiveness in melanogenesis inhibition. Bioorg Chem 81:577–586.  https://doi.org/10.1016/j.bioorg.2018.09.003 CrossRefGoogle Scholar
  27. 27.
    Khan A, Jasinski JP, Smolenski VA, Hotchkiss EP, Kelley PT, Shalit ZA, Kaur M, Paul K, Sharma R (2018) Enhancement in anti-tubercular activity of indole based thiosemicarbazones on complexation with copper(I) and silver(I) halides: structure elucidation, evaluation and molecular modelling. Bioorg Chem 80:303–318.  https://doi.org/10.1016/j.bioorg.2018.06.027 CrossRefGoogle Scholar
  28. 28.
    Feng Y, Kunos CA, Xu Y (2015) Determination of triapine, a ribonucleotide reductase inhibitor, in human plasma by liquid chromatography tandem mass spectrometry. Biomed Chromatogr 29:1380–1387.  https://doi.org/10.1002/bmc.3434 CrossRefGoogle Scholar
  29. 29.
    Heffeter P, Pape VFS, Enyedy EA, Keppler BK, Szakacs G, Kowol CR (2019) Anticancer thiosemicarbazones: chemical properties, interaction with iron metabolism, and resistance development. Antioxid Redox Signal 30:1062–1082.  https://doi.org/10.1089/ars.2017.7487 CrossRefGoogle Scholar
  30. 30.
    Vandresen F, Falzirolli H, Batista ASA, da Silva-Giardini AP, de Oliveira DN, Catharino RR, Ruiz AL, de Carvalho JE, Foglio MA, da Silva CC (2014) Novel R-(+)-limonene-based thiosemicarbazones and their antitumor activity against human tumor cell lines. Eur J Med Chem 79:110–116.  https://doi.org/10.1016/j.ejmech.2014.03.086 CrossRefGoogle Scholar
  31. 31.
    Rodrigues DSB, de Avila RI, Benfica PL, Bringel LP, de Oliveira CMA, Vandresen F, da Silva CC, Valadares MC (2018) 4-Fluorobenzaldehyde limonene-based thiosemicarbazone induces apoptosis in PC-3 human prostate cancer cells. Life Sci 203:141–149.  https://doi.org/10.1016/j.lfs.2018.04.024 CrossRefGoogle Scholar
  32. 32.
    Lee A, Djamgoz MBA (2018) Triple negative breast cancer: emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev 62:110–122.  https://doi.org/10.1016/j.ctrv.2017.11.003 CrossRefGoogle Scholar
  33. 33.
    Malik P, Mukherjee TK (2018) Recent advances in gold and silver nanoparticle based therapies for lung and breast cancers. Int J Pharm 553:483–509.  https://doi.org/10.1016/j.ijpharm.2018.10.048 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Estefany Ingrid Medina-Reyes
    • 1
  • Marco Antonio Mancera-Rodríguez
    • 1
  • Norma Laura Delgado-Buenrostro
    • 1
  • Adriana Moreno-Rodríguez
    • 2
  • Juan Luis Bautista-Martínez
    • 2
  • Clara Estela Díaz-Velásquez
    • 3
  • Stefanía Andrea Martínez-Alarcón
    • 1
  • Hugo Torrens
    • 4
  • María de los Ángeles Godínez-Rodríguez
    • 5
  • Luis Ignacio Terrazas-Valdés
    • 1
    • 3
  • Yolanda Irasema Chirino
    • 1
  • Felipe Vaca-Paniagua
    • 1
    • 3
    • 6
    Email author
  1. 1.Unidad de Biomedicina, Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantlaMexico
  2. 2.Facultad de Ciencias QuímicasUniversidad Autónoma Benito JuárezOaxacaMexico
  3. 3.Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantlaMexico
  4. 4.Facultad de QuímicaUniversidad Nacional Autónoma de MéxicoCiudad de MéxicoMéxico
  5. 5.Carrera de Enfermería, Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantlaMexico
  6. 6.Subdirección de Investigación BásicaInstituto Nacional de CancerologíaCiudad de MéxicoMexico

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