Urea and Thiourea Derivatives of Salinomycin as Agents Targeting Malignant Colon Cancer Cells


Дәйексөз келтіру

Толық мәтін

Аннотация

Background:Since it was discovered that a natural polyether ionophore called salinomycin (SAL) selectively inhibits human cancer cells, the scientific world has been paying special attention to this compound. It has been studied for nearly 15 years.

Objective:Thus, a very interesting research direction is the chemical modification of SAL structure, which could give more biologically active agents.

Methods:We evaluated the anticancer activity of (thio)urea analogues class of C20-epi-aminosalinomycin (compound 3b). The studies covered the generation of reactive oxygen species (ROS), proapoptotic activity, cytotoxic activity, and lipid peroxidation in vitro.

Results:Thioureas 5a-5d showed antiproliferative activity against selected human colon cancer cell lines greater than that of chemically unmodified SAL, with a 2~10-fold higher potency towards a metastatic variant of colon cancer cells (SW620). Mechanistically, SAL derivatives showed proapoptotic activity in primary colon cancer cells and induced the production of reactive oxygen species (ROS) in these cells. In SW620 cells, SAL derivatives increased lipid peroxidation with a weak effect on apoptosis and low ROS formation with cytotoxic effects followed by cytostatic ones, suggesting different modes of action of the compounds against primary and metastatic colon cancer cells.

Conclusion:The results of this study suggested that urea and thiourea derivatives of SAL provide promising leads for the rational development of new anticancer active agents.

Авторлар туралы

Michal Antoszczak

Department of Medical Chemistry, Faculty of Chemistry,, Adam Mickiewicz University

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Magdalena Mielczarek-Puta

Chair and Department of Biochemistry, Medical University of Warsaw

Email: info@benthamscience.net

Marta Struga

Chair and Department of Biochemistry, Medical University of Warsaw

Email: info@benthamscience.net

Adam Huczynski

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University

Email: info@benthamscience.net

Әдебиет тізімі

  1. Colorectal cancer. 2023. Available from: https://www.who.int/news-room/fact-sheets/detail/colorectal-cancer(Accessed on: 2024-04-09)
  2. Antoszczak, M.; Steverding, D.; Huczyński, A. Anti-parasitic activity of polyether ionophores. Eur. J. Med. Chem., 2019, 166, 32-47. doi: 10.1016/j.ejmech.2019.01.035 PMID: 30684869
  3. Zhou, S.; Wang, F.; Wong, E.; Fonkem, E.; Hsieh, T.C.; Wu, J.; Wu, E. Salinomycin: A novel anti-cancer agent with known anti-coccidial activities. Curr. Med. Chem., 2013, 20(33), 4095-4101. doi: 10.2174/15672050113109990199 PMID: 23931281
  4. Kevin, D.A.; Meujo, D.A.F.; Hamann, M.T. Polyether ionophores: Broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites. Expert Opin. Drug Discov., 2009, 4(2), 109-146. doi: 10.1517/17460440802661443 PMID: 23480512
  5. Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 2009, 138(4), 645-659. doi: 10.1016/j.cell.2009.06.034 PMID: 19682730
  6. Antoszczak, M. A medicinal chemistry perspective on salinomycin as a potent anticancer and anti-CSCs agent. Eur. J. Med. Chem., 2019, 164, 366-377. doi: 10.1016/j.ejmech.2018.12.057 PMID: 30611056
  7. Jiang, J.; Li, H.; Qaed, E.; Zhang, J.; Song, Y.; Wu, R.; Bu, X.; Wang, Q.; Tang, Z. Salinomycin, as an autophagy modulator - A new avenue to anticancer: A review. J. Exp. Clin. Cancer Res., 2018, 37(1), 26. doi: 10.1186/s13046-018-0680-z PMID: 29433536
  8. Klose, J.; Eissele, J.; Volz, C.; Schmitt, S.; Ritter, A.; Ying, S.; Schmidt, T.; Heger, U.; Schneider, M.; Ulrich, A. Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells. BMC Cancer, 2016, 16(1), 896. doi: 10.1186/s12885-016-2879-8 PMID: 27855654
  9. Zhou, J.; Li, P.; Xue, X.; He, S.; Kuang, Y.; Zhao, H.; Chen, S.; Zhi, Q.; Guo, X. Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. Toxicol. Lett., 2013, 222(2), 139-145. doi: 10.1016/j.toxlet.2013.07.022 PMID: 23916687
  10. Verdoodt, B.; Vogt, M.; Schmitz, I.; Liffers, S.T.; Tannapfel, A.; Mirmohammadsadegh, A. Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species. PLoS One, 2012, 7(9), e44132. doi: 10.1371/journal.pone.0044132 PMID: 23028492
  11. Dong, T.T.; Zhou, H.M.; Wang, L.L.; Feng, B.; Lv, B.; Zheng, M.H. Salinomycin selectively targets 'CD133+' cell subpopulations and decreases malignant traits in colorectal cancer lines. Ann. Surg. Oncol., 2011, 18(6), 1797-1804. doi: 10.1245/s10434-011-1561-2 PMID: 21267784
  12. Wang, Z.; Zhou, L.; Xiong, Y.; Yu, S.; Li, H.; Fan, J.; Li, F.; Su, Z.; Song, J.; Sun, Q.; Liu, S.S.; Xia, Y.; Zhao, L.; Li, S.; Guo, F.; Huang, P.; Carson, D.A.; Lu, D. Salinomycin exerts anti‐colorectal cancer activity by targeting the β‐catenin/T‐cell factor complex. Br. J. Pharmacol., 2019, 176(17), 3390-3406. doi: 10.1111/bph.14770 PMID: 31236922
  13. Klose, J.; Trefz, S.; Wagner, T.; Steffen, L.; Preißendörfer, C.A.; Radhakrishnan, P.; Volz, C.; Schmidt, T.; Ulrich, A.; Dieter, S.M.; Ball, C.; Glimm, H.; Schneider, M. Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model. PLoS One, 2019, 14(2), e0211916. doi: 10.1371/journal.pone.0211916 PMID: 30763370
  14. Antoszczak, M. A comprehensive review of salinomycin derivatives as potent anticancer and anti-CSCs agents. Eur. J. Med. Chem., 2019, 166, 48-64. doi: 10.1016/j.ejmech.2019.01.034 PMID: 30684870
  15. Versini, A.; Saier, L.; Sindikubwabo, F.; Müller, S.; Cañeque, T.; Rodriguez, R. Chemical biology of salinomycin. Tetrahedron, 2018, 74(39), 5585-5614. doi: 10.1016/j.tet.2018.07.028
  16. Li, B.; Wu, J.; Zhang, W.; Li, Z.; Chen, G.; Zhou, Q.; Wu, S. Synthesis and biological activity of salinomycin-hydroxamic acid conjugates. Bioorg. Med. Chem. Lett., 2017, 27(7), 1624-1626. doi: 10.1016/j.bmcl.2017.01.080 PMID: 28262526
  17. Borgström, B.; Huang, X.; Chygorin, E.; Oredsson, S.; Strand, D. Salinomycin hydroxamic acids: Synthesis, structure, and biological activity of polyether ionophore hybrids. ACS Med. Chem. Lett., 2016, 7(6), 635-640. doi: 10.1021/acsmedchemlett.6b00079 PMID: 27326340
  18. Antoszczak, M.; Maj, E.; Stefańska, J.; Wietrzyk, J.; Janczak, J.; Brzezinski, B.; Huczyński, A. Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin. Bioorg. Med. Chem. Lett., 2014, 24(7), 1724-1729. doi: 10.1016/j.bmcl.2014.02.042 PMID: 24631190
  19. Antoszczak, M.; Popiel, K.; Stefańska, J.; Wietrzyk, J.; Maj, E.; Janczak, J.; Michalska, G.; Brzezinski, B.; Huczyński, A. Synthesis, cytotoxicity and antibacterial activity of new esters of polyether antibiotic – Salinomycin. Eur. J. Med. Chem., 2014, 76, 435-444. doi: 10.1016/j.ejmech.2014.02.031 PMID: 24602789
  20. Czerwonka, D.; Müller, S.; Cañeque, T.; Colombeau, L.; Huczyński, A.; Antoszczak, M.; Rodriguez, R. Expeditive synthesis of potent C20-epi-amino derivatives of salinomycin against cancer stem-like cells. ACS Org. Inorg. Au, 2022, 2(3), 214-221. doi: 10.1021/acsorginorgau.1c00046 PMID: 35673680
  21. Antoszczak, M.; Müller, S.; Colombeau, L.; Cañeque, T.; Rodriguez, R. Rapid access to ironomycin derivatives by click chemistry. ACS Org. Inorg. Au, 2022, 2(3), 222-228. doi: 10.1021/acsorginorgau.1c00045 PMID: 35673682
  22. Versini, A.; Colombeau, L.; Hienzsch, A.; Gaillet, C.; Retailleau, P.; Debieu, S.; Müller, S.; Cañeque, T.; Rodriguez, R. Salinomycin derivatives kill breast cancer stem cells by lysosomal iron targeting. Chemistry, 2020, 26(33), 7416-7424. doi: 10.1002/chem.202000335 PMID: 32083773
  23. Li, Y.; Shi, Q.; Shao, J.; Yuan, Y.; Yang, Z.; Chen, S.; Zhou, X.; Wen, S.; Jiang, Z.X. Synthesis and biological evaluation of 20-epi-amino-20-deoxysalinomycin derivatives. Eur. J. Med. Chem., 2018, 148, 279-290. doi: 10.1016/j.ejmech.2018.02.004 PMID: 29466777
  24. Mai, T.T.; Hamaï, A.; Hienzsch, A.; Cañeque, T.; Müller, S.; Wicinski, J.; Cabaud, O.; Leroy, C.; David, A.; Acevedo, V.; Ryo, A.; Ginestier, C.; Birnbaum, D.; Charafe-Jauffret, E.; Codogno, P.; Mehrpour, M.; Rodriguez, R. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat. Chem., 2017, 9(10), 1025-1033. doi: 10.1038/nchem.2778 PMID: 28937680
  25. Borgström, B.; Huang, X.; Hegardt, C.; Oredsson, S.; Strand, D. Structure-activity relationships in salinomycin: Cytotoxicity and phenotype selectivity of semi-synthetic derivatives. Chemistry, 2017, 23(9), 2077-2083. doi: 10.1002/chem.201603621 PMID: 27740704
  26. Zhang, W.; Wu, J.; Li, B.; Xia, J.; Wu, H.; Wang, L.; Hao, J.; Zhou, Q.; Wu, S. Synthesis and biological activity evaluation of 20-epi-salinomycin and its 20-O-acyl derivatives. RSC Advances, 2016, 6(48), 41885-41890. doi: 10.1039/C6RA08967D
  27. Shi, Q.; Li, Y.; Bo, S.; Li, X.; Zhao, P.; Liu, Q.; Yang, Z.; Cong, H.; Deng, H.; Chen, M.; Chen, S.; Zhou, X.; Ding, H.; Jiang, Z.X. Discovery of a 19 F MRI sensitive salinomycin derivative with high cytotoxicity towards cancer cells. Chem. Commun. (Camb.), 2016, 52(29), 5136-5139. doi: 10.1039/C6CC01508E PMID: 26997457
  28. Borgström, B.; Huang, X.; Pošta, M.; Hegardt, C.; Oredsson, S.; Strand, D. Synthetic modification of salinomycin: Selective O-acylation and biological evaluation. Chem. Commun. (Camb.), 2013, 49(85), 9944-9946. doi: 10.1039/c3cc45983g PMID: 24037337
  29. Antoszczak, M.; Müller, S.; Cañeque, T.; Colombeau, L.; Dusetti, N.; Santofimia-Castaño, P.; Gaillet, C.; Puisieux, A.; Iovanna, J.L.; Rodriguez, R. Iron-sensitive prodrugs that trigger active ferroptosis in drug-tolerant pancreatic cancer cells. J. Am. Chem. Soc., 2022, 144(26), 11536-11545. doi: 10.1021/jacs.2c03973 PMID: 35696539
  30. Czerwonka, D.; Urbaniak, A.; Sobczak, S.; Piña-Oviedo, S.; Chambers, T.C.; Antoszczak, M.; Huczyński, A. Synthesis and anticancer activity of tertiary amides of salinomycin and their C20-oxo analogues. ChemMedChem, 2020, 15(2), 236-246. doi: 10.1002/cmdc.201900593 PMID: 31702860
  31. Antoszczak, M.; Urbaniak, A.; Delgado, M.; Maj, E.; Borgström, B.; Wietrzyk, J.; Huczyński, A.; Yuan, Y.; Chambers, T.C.; Strand, D. Biological activity of doubly modified salinomycin analogs – Evaluation in vitro and ex vivo. Eur. J. Med. Chem., 2018, 156, 510-523. doi: 10.1016/j.ejmech.2018.07.021 PMID: 30025346
  32. Klose, J.; Kattner, S.; Borgström, B.; Volz, C.; Schmidt, T.; Schneider, M.; Oredsson, S.; Strand, D.; Ulrich, A. Semi-synthetic salinomycin analogs exert cytotoxic activity against human colorectal cancer stem cells. Biochem. Biophys. Res. Commun., 2018, 495(1), 53-59. doi: 10.1016/j.bbrc.2017.10.147 PMID: 29107689
  33. Hu, H.; Lin, C.; Ao, M.; Ji, Y.; Tang, B.; Zhou, X.; Fang, M.; Zeng, J.; Wu, Z. Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents. RSC Advances, 2017, 7(81), 51640-51651. doi: 10.1039/C7RA08149A
  34. Chen, J.N.; Wang, X.F.; Li, T.; Wu, D.W.; Fu, X.B.; Zhang, G.J.; Shen, X.C.; Wang, H.S. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents. Eur. J. Med. Chem., 2016, 107, 12-25. doi: 10.1016/j.ejmech.2015.10.045 PMID: 26560049
  35. Koca, İ.; Özgür, A.; Coşkun, K.A.; Tutar, Y. Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety. Bioorg. Med. Chem., 2013, 21(13), 3859-3865. doi: 10.1016/j.bmc.2013.04.021 PMID: 23664495
  36. Saeed, S.; Rashid, N.; Jones, P.G.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem., 2010, 45(4), 1323-1331. doi: 10.1016/j.ejmech.2009.12.016 PMID: 20056520
  37. Li, H.Q.; Lv, P.C.; Yan, T.; Zhu, H.L. Urea derivatives as anticancer agents. Anticancer. Agents Med. Chem., 2009, 9(4), 471-480. doi: 10.2174/1871520610909040471 PMID: 19442045
  38. Antoszczak, M.; Gadsby-Davis, K.; Steverding, D.; Huczyński, A. Synthesis of urea and thiourea derivatives of C20-epi-aminosalinomycin and their activity against Trypanosoma brucei. Eur. J. Med. Chem., 2023, 250, 115241. doi: 10.1016/j.ejmech.2023.115241 PMID: 36870272
  39. Czerwonka, D.; Barcelos, Y.; Steverding, D.; Cioch, A.; Huczyński, A.; Antoszczak, M. Singly and doubly modified analogues of C20-epi-salinomycin: A new group of antiparasitic agents against Trypanosoma brucei. Eur. J. Med. Chem., 2021, 209, 112900. doi: 10.1016/j.ejmech.2020.112900 PMID: 33071053
  40. Czerwonka, D.; Mielczarek-Puta, M.; Antoszczak, M.; Cioch, A.; Struga, M.; Huczyński, A. Evaluation of the anticancer activity of singly and doubly modified analogues of C20-epi-salinomycin. Eur. J. Pharmacol., 2021, 908, 174347. doi: 10.1016/j.ejphar.2021.174347 PMID: 34265289
  41. Antoszczak, M.; Steverding, D.; Sulik, M.; Janczak, J.; Huczyński, A. Anti-trypanosomal activity of doubly modified salinomycin derivatives. Eur. J. Med. Chem., 2019, 173, 90-98. doi: 10.1016/j.ejmech.2019.03.061 PMID: 30986574
  42. Urbaniak, A.; Reed, M.R.; Fil, D.; Moorjani, A.; Heflin, S.; Antoszczak, M.; Sulik, M.; Huczyński, A.; Kupsik, M.; Eoff, R.L.; MacNicol, M.C.; Chambers, T.C.; MacNicol, A.M. Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models. Biomed. Pharmacother., 2021, 141, 111815. doi: 10.1016/j.biopha.2021.111815 PMID: 34130123
  43. Kuran, D.; Flis, S.; Antoszczak, M.; Piskorek, M.; Huczyński, A. Ester derivatives of salinomycin efficiently eliminate breast cancer cells via ER-stress-induced apoptosis. Eur. J. Pharmacol., 2021, 893, 173824. doi: 10.1016/j.ejphar.2020.173824 PMID: 33347821
  44. Michalak, M.; Lach, M.S.; Antoszczak, M.; Huczyński, A.; Suchorska, W.M. Overcoming resistance to platinum-based drugs in ovarian cancer by salinomycin and its derivatives ‒ An in vitro study. Molecules, 2020, 25(3), 537. doi: 10.3390/molecules25030537 PMID: 31991882
  45. Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. J. Immunol. Methods, 1986, 89(2), 271-277. doi: 10.1016/0022-1759(86)90368-6 PMID: 3486233
  46. Ansa, B.; Coughlin, S.; Alema-Mensah, E.; Smith, S. Evaluation of colorectal cancer incidence trends in the United States (2000–2014). J. Clin. Med., 2018, 7(2), 22. doi: 10.3390/jcm7020022 PMID: 29385768
  47. Van Cutsem, E.; Oliveira, J. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann. Oncol., 2009, 20(Suppl. 4), iv61-iv63. doi: 10.1093/annonc/mdp130 PMID: 19454465
  48. Littlejohns, P.; Tamber, S.; Ranson, P.; Campbell, B.; Adams, A.; Seymour, M.; Martin, D. Treatment for liver metastases from colorectal cancer. Lancet Oncol., 2005, 6(2), 73. doi: 10.1016/S1470-2045(05)01729-8 PMID: 15704298
  49. SEER Cancer Statistics Review (CSR) 1975-2015. 2018. Available from: https://seer.cancer.gov/archive/csr/1975_2015/index.html (accessed on: 2024‒04‒09)
  50. Yu, S.N.; Kim, S.H.; Kim, K.Y.; Ji, J.H.; Seo, Y.K.; Yu, H.S.; Ahn, S.C. Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells. Oncol. Rep., 2017, 37(6), 3321-3328. doi: 10.3892/or.2017.5615 PMID: 28498472
  51. Lin, C.S.; Liu, L.T.; Ou, L.H.; Pan, S.C.; Lin, C.I.; Wei, Y.H. Role of mitochondrial function in the invasiveness of human colon cancer cells. Oncol. Rep., 2017, 39(1), 316-330. doi: 10.3892/or.2017.6087 PMID: 29138850
  52. Cheng, Y.; Lu, Y.; Zhang, D.; Lian, S.; Liang, H.; Ye, Y.; Xie, R.; Li, S.; Chen, J.; Xue, X.; Xie, J.; Jia, L. Metastatic cancer cells compensate for low energy supplies in hostile microenvironments with bioenergetic adaptation and metabolic reprogramming. Int. J. Oncol., 2018, 53(6), 2590-2604. doi: 10.3892/ijo.2018.4582 PMID: 30280201
  53. Bajzikova, M.; Kovarova, J.; Coelho, A.R.; Boukalova, S.; Oh, S.; Rohlenova, K.; Svec, D.; Hubackova, S.; Endaya, B.; Judasova, K.; Bezawork-Geleta, A.; Kluckova, K.; Chatre, L.; Zobalova, R.; Novakova, A.; Vanova, K.; Ezrova, Z.; Maghzal, G.J.; Magalhaes Novais, S.; Olsinova, M.; Krobova, L.; An, Y.J.; Davidova, E.; Nahacka, Z.; Sobol, M.; Cunha-Oliveira, T.; Sandoval-Acuña, C.; Strnad, H.; Zhang, T.; Huynh, T.; Serafim, T.L.; Hozak, P.; Sardao, V.A.; Koopman, W.J.H.; Ricchetti, M.; Oliveira, P.J.; Kolar, F.; Kubista, M.; Truksa, J.; Dvorakova-Hortova, K.; Pacak, K.; Gurlich, R.; Stocker, R.; Zhou, Y.; Berridge, M.V.; Park, S.; Dong, L.; Rohlena, J.; Neuzil, J. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab., 2019, 29(2), 399-416.e10. doi: 10.1016/j.cmet.2018.10.014 PMID: 30449682
  54. Phan, L.M.; Yeung, S.C.; Lee, M.H. Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol. Med., 2014, 11(1), 1-19. doi: 10.7497/j.issn.2095-3941.2014.01.001 PMID: 24738035
  55. Niu, Y.; Zhou, Y.; Zheng, H.; Zhao, L.; Li, C.; Gao, H. Metabonomics analysis of colorectal carcinoma cell lines SW480 and SW620 with different metastatic potentials. J. Wezhou. Med. Univ., 2019, 49, 243-248. doi: 10.3969/j.issn.2095-9400.2019.04.002
  56. Luo, F.; Li, J.; Wu, S.; Wu, X.; Chen, M.; Zhong, X.; Liu, K. Comparative profiling between primary colorectal carcinomas and metastases identifies heterogeneity on drug resistance. Oncotarget, 2016, 7(39), 63937-63949. doi: 10.18632/oncotarget.11570 PMID: 27613840
  57. Disoma, C.; Zhou, Y.; Li, S.; Peng, J.; Xia, Z. Wnt/β-catenin signaling in colorectal cancer: Is therapeutic targeting even possible? Biochimie, 2022, 195, 39-53. doi: 10.1016/j.biochi.2022.01.009 PMID: 35066101
  58. Leiphrakpam, P.; Are, C. PI3K/Akt/mTOR signaling pathway as a target for colorectal cancer treatment. Int. J. Mol. Sci., 2024, 25(6), 3178. doi: 10.3390/ijms25063178 PMID: 38542151

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