In vitro Selective Effect of Imidazole Derivatives as Inhibitors of Human Laryngeal Carcinoma

Authors

  • Vasyl Kovalishyn Laboratory of Biomedical Research, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv-02094 (Ukraine) https://orcid.org/0000-0002-9352-7332
  • Sergiy Rogalsky Laboratory of Modification of Polymers, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv-02160 (Ukraine) https://orcid.org/0000-0002-5200-5247
  • Diana Hodyna Laboratory of Biomedical Research, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv-02094 (Ukraine) https://orcid.org/0000-0001-6161-9833
  • Petro Borysko Laboratory of Biomedical Research, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv-02094 (Ukraine); Bienta/Enamine Ltd., Kyiv-02094 (Ukraine) https://orcid.org/0000-0002-5840-5233
  • Larysa Metelytsia Laboratory of Biomedical Research, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Kyiv-02094 (Ukraine) https://orcid.org/0000-0002-9876-6076

DOI:

https://doi.org/10.47352/bioactivities.2963-654X.338

Keywords:

anticancer activity, human laryngeal carcinoma, imidazole derivatives

Abstract

Laryngeal cancer represents a significant portion of head and neck malignancies, greatly affecting quality of life. Despite advancements in treatment, late-stage mortality remains high. The HEp-2 cell line, derived from human laryngeal carcinoma, serves as an in vitro model for studying this cancer. We present in vitro results highlighting the activity of imidazole-based ionic liquids and lysosomotropic detergents as selective inhibitors of laryngeal cancer growth using the HEp-2 cell line, alongside non-oncogenic MRC-5 and HEK-293 cell lines. A comparative analysis of the selectivity coefficients reflecting the action of these imidazole derivatives on HEp-2 cancer cells, compared to their effects on MRC-5 fibroblasts and HEK-293 kidney cells, revealed that the compounds 1-dodecyl-3-methylimidazolium chloride, 1-decyloxycarbonylmethylimidazole, and 1-dodecyloxycarbonylmethyl-3-methylimidazolium chloride appear to be promising candidates with selective activity against laryngeal cancer, with anticancer selectivity coefficients ranging from 2.8 to 11.5 and 2.2 to 20.1, respectively. Especially promising is 1-dodecylimidazole, which has an average selectivity coefficient of 47,675 based on IC₅₀ values for the two non-oncogenic cell lines. Notably, the selectivity coefficients of these compounds were significantly higher—by two or more times—than those of the drug cisplatin.

References

[1] M. Fusi and S. Dotti. (2021). "Adaptation of the HEp-2 cell line to totally animal-free culture systems and real-time analysis of cell growth". BioTechniques. 70 (6): 319-326. 10.2144/btn-2020-0162.

DOI: https://doi.org/10.2144/btn-2020-0162

[2] P. Gorphe. (2019). "A comprehensive review of Hep-2 cell line in translational research for laryngeal cancer". American Journal of Cancer Research. 9 (4): 644-649.

[3] L. Zhou, T. Mudianto, X. Ma, R. Riley, and R. Uppaluri. (2020). "Targeting EZH2 enhances antigen presentation, antitumor immunity, and circumvents anti-PD-1 resistance in head and neck cancer". Clinical Cancer Research. 26 (1): 290-300. 10.1158/1078-0432.CCR-19-1351.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-1351

[4] M. D. Mody, J. W. Rocco, S. S. Yom, R. I. Haddad, and N. F. Saba. (2021). "Head and neck cancer". The Lancet. 398 (10318): 2289-2299. 10.1016/S0140-6736(21)01550-6.

DOI: https://doi.org/10.1016/S0140-6736(21)01550-6

[5] S. Ramachandran. (2024). "Oral cancer: Recent breakthroughs in pathology and therapeutic approaches". Oral Oncology Reports. 12 : 100678. 10.1016/j.oor.2024.100678.

DOI: https://doi.org/10.1016/j.oor.2024.100678

[6] A. Santos, I. C. Santos, P. F. Dos Reis, V. D. Rodrigues, and W. A. F. Peres. (2022). "Impact of nutritional status on survival in head and neck cancer patients after total laryngectomy". Nutrition and Cancer. 74 (4): 1252-1260. 10.1080/01635581.2021.1952446.

DOI: https://doi.org/10.1080/01635581.2021.1952446

[7] R. Siegel, J. Ma, Z. Zou, and A. Jemal. (2014). "Cancer statistics, 2014". CA: A Cancer Journal for Clinicians. 64 (1): 9-29. 10.3322/caac.21208.

DOI: https://doi.org/10.3322/caac.21208

[8] B. J. Baird, C. K. Sung, B. M. Beadle, and V. Divi. (2018). "Treatment of early-stage laryngeal cancer: A comparison of treatment options". Oral Oncology. 87 : 8-16. 10.1016/j.oraloncology.2018.09.012.

DOI: https://doi.org/10.1016/j.oraloncology.2018.09.012

[9] C. Liu, H. Liu, H. Huang, J. Hao, Y. Lv, J. Zhang, Y. Ma, C. Wu, R. Qin, and X. Yang. (2020). "Corilagin induces laryngeal cancer antiproliferation and inhibits growth factor and cytokine signaling pathways in vitro and in vivo". Journal of Functional Foods. 69 : 103947. 10.1016/j.jff.2020.103947.

DOI: https://doi.org/10.1016/j.jff.2020.103947

[10] D. Wang, D. Yu, X. Liu, Q. Wang, X. Chen, X. Hu, C. Jin, L. Wen, and L. Zhang. (2020). "Targeting laryngeal cancer cells with 5-fluorouracil and curcumin using mesoporous silica nanoparticles". Technology in Cancer Research & Treatment. 19 : 1533033820962114. 10.1177/1533033820962114.

DOI: https://doi.org/10.1177/1533033820962114

[11] R. F. M. Elshaarawy and C. Janiak. (2016). "Antibacterial susceptibility of new copper(II) N-pyruvoyl anthranilate complexes against marine bacterial strains: In search of new antibiofouling candidate". Arabian Journal of Chemistry. 9 (6): 825-834. 10.1016/j.arabjc.2015.04.010.

DOI: https://doi.org/10.1016/j.arabjc.2015.04.010

[12] M. Kielbus, K. Skalicka-Woźniak, A. Grabarska, W. Jeleniewicz, M. Dmoszyńska-Graniczka, A. Marston, K. Polberg, P. Gawda, J. Klatka, and A. Stepulak. (2013). "7-substituted coumarins inhibit proliferation and migration of laryngeal cancer cells in vitro". Anticancer Research. 33 (10): 4347-4356.

[13] B. Haznedar, N. Bayar Muluk, C. Vejselova Sezer, H. M. Kutlu, and C. Cingi. (2024). "Investigation of proapoptotic and cytotoxic effects of 2-aminobenzothiazole on human laryngeal carcinoma cells". European Review for Medical and Pharmacological Sciences. 28 (4): 1585-1593. 10.26355/eurrev_202402_35487.

[14] X. Kong, R. Zhang, Y. Shen, Y. Bai, K. Dong, D. Li, and Y. Wang. (2022). "Preparation and inhibitory effect of salicin dimethyl ether in laryngeal cancer cells through apoptosis activation". Acta Biochimica Polonica. 69 (4): 753-759. 10.18388/abp.2020_5990.

DOI: https://doi.org/10.18388/abp.2020_5990

[15] A. Rana, J. M. Alex, M. Chauhan, G. Joshi, and R. Kumar. (2015). "A review on pharmacophoric designs of antiproliferative agents". Medicinal Chemistry Research. 24 : 903-920. 10.1007/s00044-014-1196-5.

DOI: https://doi.org/10.1007/s00044-014-1196-5

[16] A. Zafar, S. Khatoon, M. J. Khan, J. Abu, and A. Naeem. (2025). "Advancements and limitations in traditional anti-cancer therapies: A comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy". Discover Oncology. 16 (1): 607. 10.1007/s12672-025-02198-8.

DOI: https://doi.org/10.1007/s12672-025-02198-8

[17] A. Gryniukova, P. Borysko, I. Myziuk, D. Alieksieieva, D. Hodyna, I. Semenyuta, V. Kovalishyn, L. Metelytsia, S. Rogalsky, and S. Tcherniuk. (2024). "Anticancer activity features of imidazole-based ionic liquids and lysosomotropic detergents: In silico and in vitro studies". Molecular Diversity. 28 (6): 3817-3833. 10.1007/s11030-023-10779-4.

DOI: https://doi.org/10.1007/s11030-023-10779-4

[18] D. Hodyna, V. Kovalishyn, I. Semenyuta, S. Rogalsky, O. Trokhimenko, O. Gryniukova, and L. Metelytsia. (2022). "Ester-functionalized imidazolium- and pyridinium-based ionic liquids: Design, synthesis and cytotoxicity evaluation". Biointerface Research in Applied Chemistry. 12 (3): 2905-2957. 10.33263/BRIAC123.29052957.

DOI: https://doi.org/10.33263/BRIAC123.29052957

[19] C. Nassour, S. Nabhani-Gebara, S. J. Barton, and J. Barker. (2021). "Aquatic ecotoxicology of anticancer drugs: A systematic review". Science of the Total Environment. 800 : 149598. 10.1016/j.scitotenv.2021.149598.

DOI: https://doi.org/10.1016/j.scitotenv.2021.149598

[20] A. Białk-Bielińska, E. Mulkiewicz, M. Stokowski, S. Stolte, and P. Stepnowski. (2017). "Acute aquatic toxicity assessment of six anti-cancer drugs and one metabolite using biotest battery: Biological effects and stability under test conditions". Chemosphere. 189 : 689-698. 10.1016/j.chemosphere.2017.08.174.

DOI: https://doi.org/10.1016/j.chemosphere.2017.08.174

[21] O. OECD. (2004). "OECD guidelines for the testing of chemicals, Section 2: Effects on biotic systems—Test No. 202: Daphnia sp. acute immobilisation test". OECD Publishing. 10.1787/20745761

DOI: https://doi.org/10.1787/20745761

[22] D. R. M. Passino and S. B. Smith. (1987). "Acute bioassays and hazard evaluation of representative contaminants detected in Great Lakes fish". Environmental Toxicology and Chemistry. 6 (11): 901-907. 10.1002/etc.5620061111.

DOI: https://doi.org/10.1002/etc.5620061111

[23] Q. Fang, X. Li, P. Xu, F. Cao, D. Wu, X. Zhang, C. Chen, J. Gao, Y. Su, and X. Liu. (2024). "PD-1 inhibitor combined with paclitaxel and cisplatin in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma: Efficacy and survival outcomes". Frontiers in Immunology. 15 : 1353435. 10.3389/fimmu.2024.1353435.

DOI: https://doi.org/10.3389/fimmu.2024.1353435

[24] A. A. Forastiere, H. Goepfert, M. Maor, T. F. Pajak, R. Weber, W. Morrison, B. Glisson, A. Trotti, J. A. Ridge, C. Chao, G. Peters, D. J. Lee, A. Leaf, J. Ensley, and J. Cooper. (2003). "Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer". The New England Journal of Medicine. 349 (22): 2091-2098. 10.1056/NEJMoa031317.

DOI: https://doi.org/10.1056/NEJMoa031317

[25] A. Remesh. (2017). "Toxicities of anticancer drugs and its management". International Journal of Basic & Clinical Pharmacology. 1 (1): 2-12. 10.5455/2319-2003.ijbcp000812.

DOI: https://doi.org/10.5455/2319-2003.ijbcp000812

[26] A. Gupta, E. A. Eisenhauer, and C. M. Booth. (2022). "The time toxicity of cancer treatment". Journal of Clinical Oncology. 40 (15): 1611-1615. 10.1200/JCO.21.02810.

DOI: https://doi.org/10.1200/JCO.21.02810

[27] Y. T. Lee, Y. J. Tan, and C. E. Oon. (2018). "Molecular targeted therapy: Treating cancer with specificity". European Journal of Pharmacology. 834 : 188-196. 10.1016/j.ejphar.2018.07.034.

DOI: https://doi.org/10.1016/j.ejphar.2018.07.034

[28] H. Yao, G. He, S. Yan, C. Chen, L. Song, T. J. Rosol, and X. Deng. (2017). "Triple-negative breast cancer: Is there a treatment on the horizon?". Oncotarget. 8 (1): 1913-1924. 10.18632/oncotarget.12284.

DOI: https://doi.org/10.18632/oncotarget.12284

[29] S. M. Ding, J. F. Lu, M. I. A. Edoo, L. Zhou, H. Y. Xie, S. S. Zheng, and Q. Y. Li. (2019). "MRC-5 cancer-associated fibroblasts influence production of cancer stem cell markers and inflammation-associated cell surface molecules in liver cancer cell lines". International Journal of Medical Sciences. 16 (8): 1157-1170. 10.7150/ijms.34758.

DOI: https://doi.org/10.7150/ijms.34758

[30] N. Hayashi, A. Yamasaki, S. Ueda, S. Okazaki, Y. Ohno, T. Tanaka, Y. Endo, Y. Tomioka, K. Masuko, T. Masuko, and R. Sugiura. (2021). "Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target". Oncotarget. 12 (13): 1256-1270. 10.18632/oncotarget.27981.

DOI: https://doi.org/10.18632/oncotarget.27981

[31] A. A. Stepanenko and V. V. Dmitrenko. (2015). "HEK293 in cell biology and cancer research: Phenotype, karyotype, tumorigenicity, and stress-induced genome–phenotype evolution". Gene. 569 (2): 182-190. 10.1016/j.gene.2015.05.065.

DOI: https://doi.org/10.1016/j.gene.2015.05.065

[32] F. Tavares-Carreón, S. De la Torre-Zavala, H. F. Arocha-Garza, V. Souza, L. J. Galán-Wong, and H. Avilés-Arnaut. (2020). "In vitro anticancer activity of methanolic extract of Granulocystopsis sp., a microalgae from an oligotrophic oasis in the Chihuahuan Desert". PeerJ. 8 : e8686. 10.7717/peerj.8686.

DOI: https://doi.org/10.7717/peerj.8686

[33] J. R. Choi, G. Kozalak, I. di Bari, Q. Babar, Z. Niknam, Y. Rasmi, and K. W. Yong. (2022). "In vitro human cancer models for biomedical applications". Cancers. 14 (9): 2284. 10.3390/cancers14092284.

DOI: https://doi.org/10.3390/cancers14092284

[34] H. J. Kao, T. H. Weng, C. H. Chen, Y. C. Chen, Y. H. Chi, K. Y. Huang, and S. L. Weng. (2024). "Integrating in silico and in vitro approaches to identify natural peptides with selective cytotoxicity against cancer cells". International Journal of Molecular Sciences. 25 (13): 6848. 10.3390/ijms25136848.

DOI: https://doi.org/10.3390/ijms25136848

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Published

2025-12-30

How to Cite

Kovalishyn, V., Rogalsky, S., Hodyna, D., Borysko, P., & Metelytsia, L. (2025). In vitro Selective Effect of Imidazole Derivatives as Inhibitors of Human Laryngeal Carcinoma. Bioactivities, 3(2), 124–133. https://doi.org/10.47352/bioactivities.2963-654X.338

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Vol. 3 No. 2 (2025): Bioactivities

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Copyright (c) 2025 Vasyl Kovalishyn, Sergiy Rogalsky, Diana Hodyna, Petro Borysko, Larysa Metelytsia

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