Abstract
Background
Ovarian cancer, also known as a silent killer, is the deadliest gynecological cancer in women worldwide. Epithelial ovarian cancers constitute the majority of ovarian cancers, and diagnosis can be made in advanced stages, which greatly reduces the likelihood of treatment and lowers the survival rate. For the treatment of epithelial ovarian cancers, the search for synthetic agents as well as agents of natural origin continues. The effects of 1-(2-cyanobenzyl)-3-(4-vinylbenzyl)-1H-benzo[d]imidazole-3-ium chloride (BD), a benzimidazole derivative, were investigated on epithelial ovarian cancer cells.
Methods and results
In our study, the effects of BD on proliferation, colony formation, cell death by apoptosis and the cell cycle in A2780 and A2780 Adriamycin (ADR) ovarian cancer cell lines were investigated. Proliferation was examined with cell viability analysis, colony formation and apoptosis with Annexin V staining and cell cycle analyses with PI staining, respectively. As a result of the analyses, BD inhibited cell proliferation and colony formation, induced apoptosis and cell death at 48 h in A2780 and A2780 ADR cells at 10.10 and 10.36 µM concentrations, respectively. In addition, A2780 and A2780ADR cells were arrested in the Sub-G1 phase of the cell cycle.
Conclusions
BD suppresses cancer cell progression by showing antiproliferative effects on ovarian cancer cells. Further analyses are required to determine the mechanism of action of this agent and to demonstrate its potential as a suitable candidate for the treatment of epithelial ovarian cancer.
Similar content being viewed by others
Data availability
Not applicaple.
Change history
27 March 2024
A Correction to this paper has been published: https://doi.org/10.1007/s11033-024-09413-9
References
Luvero D et al (2019) Ovarian cancer relapse: from the latest scientific evidence to the best practice. Crit Rev Oncol Hematol 140:28–38
Williams TI et al (2007) Epithelial ovarian cancer: disease etiology, treatment, detection, and investigational gene, metabolite, and protein biomarkers. J Proteome Res 6(8):2936–2962
Kossai M et al (2018) Ovarian cancer: a heterogeneous disease. Pathobiology 85(1–2):41–49
Jayde V, White K, Blomfield P (2009) Symptoms and diagnostic delay in ovarian cancer: a summary of the literature. Contemp Nurse 34(1):55–65
Mahoney DE, Pierce JD (2022) Ovarian cancer symptom clusters: use of the NIH symptom science model for precision in symptom recognition and management. Clin J Oncol Nurs 26(5):533–542
Sehouli J, Grabowski JP (2019) Surgery in recurrent ovarian cancer. Cancer 125:4598–4601
O’Malley DM (2019) New therapies for ovarian cancer. J Natl Compr Cancer Netw 17(55):619–621
Yang L et al (2022) Molecular mechanisms of platinum–based chemotherapy resistance in ovarian cancer (review). Oncol Rep 47:1
Akkoç S, Kayser V, İlhan İÖ (2019) Synthesis and in vitro anticancer evaluation of some benzimidazolium salts. J Heterocycl Chem 56(10):2934–2944
Bansal Y, Silakari O (2012) The therapeutic journey of benzimidazoles: a review. Bioorg Med Chem 20(21):6208–6236
Blaszczak-Swiatkiewicz K, Mikiciuk-Olasik E (2015) Some characteristics of activity of potential chemotherapeutics–benzimidazole derivatives. Adv Med Sci 60(1):125–132
Antoci V et al (2020) Bis-(imidazole/benzimidazole)-pyridine derivatives: synthesis, structure and antimycobacterial activity. Future Med Chem 12(3):207–222
Shingalapur RV et al (2010) Derivatives of benzimidazole pharmacophore: synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur J Med Chem 45(5):1753–1759
Azahar NH et al (2019) Mutagenic study of benzimidazole derivatives with (+S9) and without (-S9) metabolic activation. Int J Mol Sci 20(18):4324
Akar S, Donmez-Altuntas H, Hamurcu Z (2022) Beta-escin reduces cancer progression in aggressive MDA-MB-231 cells by inhibiting glutamine metabolism through downregulation of c-myc oncogene. Mol Biol Rep 49(8):7409–7415
Acikgoz E et al (2021) Metformin eliminates CD133high/CD44high prostate cancer stem cells via cell cycle arrest and apoptosis. Ejmo 5(4):298–304
Akar S, DönmezAltuntaş H, Hamurcu Z (2022) Downregulation of glutaminase 1 (GLS1) inhibits proliferation, clonogenicity, and migration of aggressive MDA-MB-231 breast cancer cells by increasing p21 and decreasing integrin-β1 expression. Erciyes Med J 44(6):587–593
Chien J, Poole EM (2017) Ovarian cancer prevention, screening, and early detection: report from the 11th biennial ovarian cancer research symposium. Int J Gynecol Cancer 27(S5):1
Alzhrani ZMM, Alam MM, Nazreen S (2022) Recent advancements on benzimidazole: a versatile Scaffold in medicinal chemistry. Mini Rev Med Chem 22:365–386
Wu K, Peng X, Chen M, Li Y, Tang G, Peng J, Peng Y, Cao X (2022) Recent progress of research on anti-tumor agents using benzimidazole as the structure unit. Chem Biol Drug Des 99:736–757
Shrivastava N et al (2017) Benzimidazole Scaffold as anticancer agent: synthetic approaches and structure-activity relationship. Arch Pharm (Weinheim) 350(6):e201700040
Cui AL et al (2022) Synthesis and anti-ovarian cancer effects of benzimidazole-2-substituted pyridine and phenyl propenone derivatives. Future Med Chem 14(24):1835–1846
Abdelhafiz AHA et al (2022) Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells. J Enzyme Inhib Med Chem 37(1):2710–2724
Tyagi YK, Jali G, Singh R (2022) Synthesis and anti-cancer applications of benzimidazole derivatives - recent studies. Anticancer Agents Med Chem 22(19):3280–3290
Rajendran V, Jain MV (2018) Vitro tumorigenic assay: colony forming assay for cancer stem cells. Methods Mol Biol 1692:89–95
Elayapillai S et al (2021) Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer. Gynecol Oncol 160(1):302–311
Choi HS et al (2021) Anticancer effect of benzimidazole derivatives, especially mebendazole, on triple-negative breast cancer (TNBC) and radiotherapy-resistant TNBC in vivo and in vitro. Molecules 26(17):5118
Zhen Y et al (2020) Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in triple-negative breast cancer. Theranostics 10(18):8080–8097
Dadashpour S, Kucukkilinc TT, Ercan A, Hosseinimehr SJ, Naderi N, Irannejad H (2019) Synthesis and anticancer activity of benzimidazole/benzoxazole substituted triazolotriazines in hepatocellular carcinoma. Anticancer Agents Med Chem 19:2120–2129
Gurkan-Alp AS, Alp M, Karabay AZ, Koc A, Buyukbingol E (2020) Synthesis of some benzimidazole-derived molecules and their effects on PARP-1 activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer cell viability. Anticancer Agents Med Chem 20:1728–1738
Ren B et al (2021) Design, synthesis and in vitro antitumor evaluation of novel pyrazole-benzimidazole derivatives. Bioorg Med Chem Lett 43:128097
Rahimifard M et al (2021) Assessment of cytotoxic effects of new derivatives of pyrazino[1,2-a] benzimidazole on isolated human glioblastoma cells and mitochondria. Life Sci 286:120022
Akhtar MJ et al (2018) Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors. Bioorg Chem 78:158–169
Yoon YK et al (2014) Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities. Bioorg Med Chem 22(2):703–710
Wang S et al (2019) Structure-based design of novel benzimidazole derivatives as Pin1 inhibitors. Molecules 24(7):1198
Dembic Z (2020) Antitumor drugs and their targets. Molecules 25(23):5776
Nazreen S et al (2022) Cell cycle arrest and apoptosis-inducing ability of benzimidazole derivatives: design, synthesis, docking, and biological evaluation. Molecules 27(20):6899
Atmaca H et al (2020) Novel benzimidazole derivatives: synthesis, in vitro cytotoxicity, apoptosis and cell cycle studies. Chem Biol Interact 327:109163
Liu S et al (2016) 4-Terpineol exhibits potent in vitro and in vivo anticancer effects in Hep-G2 hepatocellular carcinoma cells by suppressing cell migration and inducing apoptosis and sub-G1 cell cycle arrest. J BUON 21(5):1195–1202
Kashyap D, Garg VK, Goel N (2021) Intrinsic and extrinsic pathways of apoptosis: role in cancer development and prognosis. Adv Protein Chem Struct Biol 125:73–120
Funding
This work was supported by Van Yuzuncu Yıl University Research Fund [Grant Number TSA-2021-9347].
Author information
Authors and Affiliations
Contributions
All authors contributed to the concept and design of the study. The design and synthesis of the benzimidazolium salt used in the study was carried out by Senem AKKOC. Material preparation, data collection and analysis were carried out by [Sakine AKAR], [Mustafa CAKIR] and [Halil OZKOL]. The first draft of the article was written by [Sakine AKAR], and all authors commented on previous versions of the article. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors have no relevant financial or non-financial interests to disclose.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised: The author 'Berna Ozdem' affiliated with 'Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, Malatya, Turkey' is included as fifth author in the article.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Akar, S., Cakir, M., Ozkol, H. et al. A benzimidazolium salt induces apoptosis and arrests cells at sub-G1 phase in epithelial ovarian cancer cells. Mol Biol Rep 51, 66 (2024). https://doi.org/10.1007/s11033-023-08981-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11033-023-08981-6