International Journal of Drug Delivery Technology
Volume 14, Issue 2

Mebendazole Suppresses Tumor Growth and Hinders the Invasion of Triple-Negative Breast Cancer in Model Systems by Disrupting RAN- GTP Regulation

Rahmeh Saad Al-Ramamneh,1,2* Mohamed El-Tanani,1,3 Frezah Muhana,1 Moath Alqaraleh2

1Faculty of Pharmacy, Pharmacological and Diagnostic Research Center (PDRC), Al-Ahliyya Amman University, Amman, Jordan.

2Faculty of Science, Department of Medical Laboratory Sciences, Al-Balqa Applied University, Al-Salt, Jordan.

3Faculty of Pharmacy. RAK Medical & Health Sciences University, Ras Al Khaimah. 

Received: 04th March, 2024; Revised: 24th March, 2024; Accepted: 19th May, 2024; Available Online: 25th June, 2024 

ABSTRACT

Due to the lack of targeted therapies, triple-negative breast cancer (TNBC), one of the most aggressive types of cancer, has a poor prognosis and a high death rate. TNBC frequently metastasizes to the brain, bones, and lungs. Studies have demonstrated a correlation between the metastatic behavior of A594 lung cancer cells and MDA-MB-231 breast cancer cells and the overexpression of the RAN GTP (RAN) gene. Using a variety of biological assays, this study sought to investigate mebendazole’s potential as an anticancer agent by specifically targeting the RAN gene. Both MDA-MB-231 breast cancer cells (IC50 7.5 µM) and A549 lung cancer cells (IC50 48.5 µM) were shown to be resistant to mebendazole’s ability to promote cell growth. The cytotoxic effect of mebendazole via the apoptotic pathway was confirmed by Annexin V assays on both cell lines. Furthermore, mebendazole demonstrated enhanced efficacy against TNBC by halting the cell cycle, preventing colony formation, invasion, and migration, and reducing RAN GTPase expression in both cell lines.

Keywords: Apoptosis, Metastasis, Migration, Proliferation, Ran-GTP, TNBC. International Journal of Drug Delivery Technology (2024); DOI: 10.25258/ijddt.14.2.62

How to cite this article: Al-Ramamneh RS, El-Tanani M, Muhana F, Alqaraleh M. Mebendazole Suppresses Tumor Growth and Hinders the Invasion of Triple-Negative Breast Cancer in Model Systems by Disrupting RAN-GTP Regulation. International Journal of Drug Delivery Technology. 2024;14(2):1011-1018.

REFERENCES

  1. Piña-Sánchez P, Chávez-González A, Ruiz-Tachiquín M, Vadillo E, Monroy-García A, Montesinos JJ, et al. Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective. Cancer Control : Journal of the Moffitt Cancer Center [Internet]. 2021 Sep 27 [cited 2022 Feb 28];28:10732748211038735.
  2. Gao Y, Liu M, Shi S, Sun Y, Li M, Zhang M, et al. Diagnostic value of seven biomarkers for breast cancer: an overview with evidence mapping and indirect comparisons of diagnostic test accuracy. Clinical and Experimental Medicine. 2020 Jan 1;20(1):97–108.
  3. Garrido-Castro AC, Lin NU, Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discovery. 2019 Jan 24;9(2):176–98.
  4. Yang R, Li Y, Wang H, Qin T, Yin X, Ma Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy. Molecular Biomedicine. 2022 Mar 4;3(1).
  5. TAMURA T, KURISHIMA K, NAKAZAWA K, KAGOHASHI K, ISHIKAWA H, SATOH H, et al. Specific organ metastases and survival in metastatic non-small-cell lung Molecular and Clinical Oncology [Internet]. 2014 Sep 4;3(1):217–21.
  6. Wang R, Yin Z, Liu L, Gao W, Li W, Shu Y, et Second Primary Lung Cancer After Breast Cancer: A Population-Based Study of 6,269 Women. Frontiers in Oncology. 2018 Oct 9;8.
  7. Kilburn LS, Johnson L, Bliss JM, Tutt AN. 0186 Treatment options for locally advanced or metastatic triple negative breast cancer: A survey of current UK practice. The Breast. 2009 Mar;18:S65.
  8. Jordan K, Schaffrath J, Jahn F, Mueller-Tidow C, Jordan B. Neuropharmacology and Management of Chemotherapy-Induced Nausea and Vomiting in Patients with Breast Cancer. Breast Care. 2014;9(4):246–53.
  9. Jiang WG, Grimshaw D, Lane J, Martin TA, Abounder R, Laterra J, et al. A hammerhead ribozyme suppresses expression of hepatocyte growth factor/scatter factor receptor c-MET and reduces migration and invasiveness of breast cancer cells. PubMed. 2001 Aug 1;7(8):2555–62.
  10. Ponzo MG, Lesurf R, Petkiewicz S, O’Malley FP, Dushanthi Pinnaduwage, Andrulis IL, et Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proceedings of the National Academy of Sciences of the United States of America. 2009 Aug 4;106(31):12903–8.
  11. Hetzer M, Gruss OJ, Mattaj The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nature Cell Biology. 2002 Jul;4(7):E177–84.
  12. Rottiers V, Näär MicroRNAs in Metabolism and Metabolic Disorders. Nature reviews Molecular cell biology [Internet]. 2012 Mar 22;13(4):239–50.
  13. Wang X, Li D, Sun L, Shen G, Liu H, Guo H, et Regulation of the small GTPase Ran by miR-802 modulates proliferation and metastasis in colorectal cancer cells. British Journal of Cancer. 2020 Mar 25;122(11):1695–706.
  14. Boudhraa Z, Carmona E, Provencher D, Mes-Masson AM. Ran GTPase: A Key Player in Tumor Progression and Metastasis. Frontiers in Cell and Developmental Biology [Internet]. 2020 May 26;8:345.
  15. Al-Karmalawy AA, Khattab M. Molecular modelling of mebendazole polymorphs as a potential colchicine binding site inhibitor. New Journal of Chemistry. 2020;44(33):13990–6.
  16. Elayapillai S, Ramraj S, Benbrook DM, Bieniasz M, Wang L, Pathuri G, et al. Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer. Gynecologic Oncology. 2021 Jan;160(1):302–11.
  17. Kapadia GJ, Ingrid, Rao GS, Fernanda Rafacho Badoco, Ricardo Andrade Furtado, Mariana Beltrame Corrêa, et al. Antiparasitic activity of menadione (vitamin K3) against Schistosoma mansoni in BABL/c mice. Acta Tropica. 2017 Mar 1;167:163–73.
  18. Tong K, Xin C, Chen Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line via the mitochondria- mediated pathway. Oncology Letters. 2016 Nov 15;13(1):518–24.
  19. Loor G, Kondapalli J, Schriewer JM, Chandel NS, Vanden Hoek TL, Schumacker PT. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radical Biology and Medicine. 2010 Dec;49(12):1925–36.
  20. Hoon Sik Choi, Young Shin Ko, Jin H, Ki Mun Kang, In Bong Ha, Jeong H, et al. Mebendazole Increases Anticancer Activity of Radiotherapy in Radiotherapy-Resistant Triple-Negative Breast Cancer Cells by Enhancing Natural Killer Cell-Mediated Cytotoxicity. International Journal of Molecular 2022 Dec 7;23(24):15493–3.
  21. Guerini AE, Triggiani L, Maddalo M, Bonù ML, Frassine F, Baiguini A, et al. Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature. Cancers [Internet]. 2019 Sep 1 [cited 2020 May 20];11(9):1284.
  22. Pinto LC, Soares BM, Pinheiro J de JV, Riggins GJ, Assumpção PP, Burbano RMR, et al. The anthelmintic drug mebendazole inhibits growth, migration and invasion in gastric cancer cell model. Toxicology in Vitro. 2015 Dec;29(8):2038–44.
  23. Li, S. Demir, Á. Del Río-Álvarez, R. Maxwell, A. Wagner,J. Carrillo-Reixach, C. Armengol, C. Vokuhl, B. Häberle, D. Von Schweinitz, I. Schmid, S. Cairo, R. Kappler, ‘Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma’, Cancers (Basel) 2022, 14, 4196.
  24. Chen X, Xu Y, Wang X, Lin P, Cao B, Zeng Y, et Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis. Acta Pharmacologica Sinica. 2019 Jun 13;40(12):1568–77.
  25. Osada, H. Tomita, Y. Tanaka, Y. Tokuyama, H. Tanaka, F. Sakashita, T. Takahashi, ‘The Utility of Vitamin K3 (Menadione) Against Pancreatic Cancer’, Anticancer Res. 2008, 28, 45–50.
  26. Sheng C, Qiu J, Wang Y, He Z, Wang H, Wang Q, et al. Knockdown of Ran GTPase expression inhibits the proliferation and migration of breast cancer Molecular Medicine Reports. 2018 May 3;
  27. Yuen H, Vignesh Gunasekharan, Chan K, Zhang S, Platt-Higgins A, Gately K, et RanGTPase: A Candidate for Myc-Mediated Cancer Progression. JNCI: Journal of the National Cancer Institute. 2013 Mar 6;105(7):475–88.
  28. Haggag, B. Abu Ras, Y. El-Tanani, M. M. Tambuwala, P.McCarron, M. Isreb, M. El-Tanani, ‘Co-Delivery of a RanGTP Inhibitory Peptide and Doxorubicin using Dual-Loaded Liposomal Carriers to Combat Chemotherapeutic Resistance in Breast Cancer Cells’, Expert Opin. Drug Deliv. 2020, 17, 1655–1669.
  29. Anaaa H ., Muhanab F ., El-Tanania M ., Madic R ., Kerfanc R . Mebendazole Loaded Nanoparticles for Lung Cancer Therapy. INTERNATIONAL JOURNAL OF DRUG DELIVERY 2022 Jun 30;12(03):1053–65.
  30. Yuen HF, Chan KK, Grills C, Murray JT, Platt-Higgins A, Eldin OS, et Ran Is a Potential Therapeutic Target for Cancer Cells with Molecular Changes Associated with Activation of the PI3K/ Akt/mTORC1 and Ras/MEK/ERK Pathways. Clinical Cancer Research [Internet]. 2012 Jan 15;18(2):380–91. Available from: https://aacrjournals.org/clincancerres/article/18/2/380/77478/ Ran-Is-a-Potential-Therapeutic-Target-for-Cancer