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
- 91 Downloads
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.
KeywordsThiosemicarbazones Cytoskeleton disruption Mitochondrial dysfunction Breast cancer cells Lung cancer cells
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.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 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
- 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
- 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
- 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.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
- 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.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.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
- 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.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.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
- 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.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