Skip to main content

Advertisement

SpringerLink
Log in

In vitro and in vivo anticancer activity of mebendazole in colon cancer: a promising drug repositioning

  • Research
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

A Correction to this article was published on 21 November 2023

This article has been updated

Abstract

Colon cancer is one of the most common cancers and one of the main causes of death worldwide. Therefore, new treatment methods with better efficiency and fewer risks are very necessary. Mebendazole (MBZ), a drug commonly used for helminthic infections, has recently received attention as a suitable candidate for the treatment of various cancers. This study aimed to investigate, in vitro and in vivo, anticancer activity and selectivity Index of MBZ on colon cancer. HT-29 (human colorectal adenocarcinoma) and MCF-10 (non-tumorigenic epithelial) cell lines were treated with MBZ and Doxorubicin (DOX; positive control drug). IC50 values were estimated using methyl thiazole diphenyl-tetrazolium bromide (MTT) assay. We employed flow cytometry using annexin V-FITC and propidium iodide dyes. For the animal study, colon cancer was subcutaneously induced by CT26 cells (mouse colon cancer) in Bulb/C mice. The mice were treated with 0.05 of LD50, intraperitoneal, every other day for 35 days. Finally, the survival rate, tumor volume, and tumor weight were calculated. Our results demonstrated that IC50 values after 72 h for HT29 and MCF-10 cell lines were 0.29 ± 0.04 µM and 0.80 ± 0.02 µM, respectively. MBZ was more selective than DOX in inhibiting the proliferation of cancer cells compared to normal cells (2. 75 vs. 2.45). Annexin V/PI staining demonstrated that MBZ treatment at IC50 concentrations induced (78 ± 12%) apoptosis in the HT29 cancer cell line after 48 h (P ≤ 0.0001). Also, in mice bearing colon cancer, MBZ significantly reduced the tumor volume (1177 ± 1109 mm3; P ≤ 0.001) and tumor weight (2.30 ± 1.97 g; P ≤ 0.0001) compared to the negative control group (weight 12.45 ± 2.0 g; volume 7346 ± 1077). Also, MBZ increases mean survival time (MST) and increase life span (ILS) percentage in the animal study (51.2 ± 37% vs 93%, respectively). This study suggests that mebendazole strongly and selectively inhibits proliferation and induces apoptosis in colon cancer cells. It may be, accordingly, a promising drug for clinical research and application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Change history

References

  • Adan A, Alizada G, Kiraz Y, Baran Y, Nalbant A (2017) Flow cytometry: basic principles and applications. Crit Rev Biotechnol 37(2):163–176

    Article  CAS  PubMed  Google Scholar 

  • Bai R-Y, Staedtke V, Aprhys CM, Gallia GL, Riggins GJ (2011) Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncol 13(9):974–982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biller LH, Schrag D (2021) Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 325(7):669–685

    Article  CAS  PubMed  Google Scholar 

  • Blom K, Rubin J, Berglund M, Jarvius M, Lenhammar L, Parrow V, Andersson C, Loskog A, Fryknäs M, Nygren P (2019) Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition. BMC Research Notes 12(1):1–7

    Article  Google Scholar 

  • Chhikara BS, Parang K (2023) Global Cancer Statistics 2022: the trends projection analysis. Chem Biol Lett 10(1):451–451

    Google Scholar 

  • da Silva EL , Mesquita FP, Aragão DR, Sousa Portilho de AJ, Marinho AD, Oliveira de LLB, Lima LB, Moraes de MEA, Montenegro RC (2023) Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death. Toxicol Appl Pharmacol: 116630

  • De Witt M, Gamble A, Hanson D, Markowitz D, Powell C, Al Dimassi S, Atlas M, Boockvar J, Ruggieri R, Symons M (2017) Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. Mol Med 23(1):50–56

    Article  PubMed  PubMed Central  Google Scholar 

  • Demirgan R, Karagöz A, Pekmez M, Önay-Uçar E, Artun FT, Gürer Ç, Mat A (2016) In vitro anticancer activity and cytotoxicity of some papaver alkaloids on cancer and normal cell lines. Afr J Tradit Complement Altern Med 13(3):22–26

    Article  CAS  Google Scholar 

  • Freshney RI (2015) Culture of animal cells: a manual of basic technique and specialized applications. John Wiley & Sons

    Google Scholar 

  • Guerini AE, Triggiani L, Maddalo M, Bonù ML, Frassine F, Baiguini A, Alghisi A, Tomasini D, Borghetti P, Pasinetti N (2019) Mebendazole as a candidate for drug repurposing in oncology: an extensive review of current literature. Cancers 11(9):1284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegazy SK, El-Azab GA, Zakaria F, Mostafa MF, El-Ghoneimy RA (2022) Mebendazole; from an anti-parasitic drug to a promising candidate for drug repurposing in colorectal cancer. Life Sci 299:120536

    Article  CAS  PubMed  Google Scholar 

  • Huang L, Zhao L, Zhang J, He F, Wang H, Liu Q, Shi D, Ni N, Wagstaff W, Chen C (2021) Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways. Aging (Albany NY) 13(13):17407

    Article  CAS  PubMed  Google Scholar 

  • Jayanthi M (2020) Evaluation of anticancer activity of ethanol extract of Leucas aspera flower. Int J Green Pharm (IJGP) 14(03)

  • Lai SR, Castello S, Robinson A, Koehler J (2017) In vitro anti-tubulin effects of mebendazole and fenbendazole on canine glioma cells. Vet Comp Oncol 15(4):1445–1454

    Article  CAS  PubMed  Google Scholar 

  • Larsen AR, Bai R-Y, Chung JH, Borodovsky A, Rudin CM, Riggins GJ, Bunz F (2015) Repurposing the antihelmintic mebendazole as a hedgehog inhibitorrepurposing mebendazole as a hedgehog inhibitor. Mol Cancer Ther 14(1):3–13

    Article  CAS  PubMed  Google Scholar 

  • Laudisi F, Marônek M, Di Grazia A, Monteleone G, Stolfi C (2020) Repositioning of anthelmintic drugs for the treatment of cancers of the digestive system. Int J Mol Sci 21(14):4957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mansoori S, Fryknäs M, Alvfors C, Loskog A, Larsson R, Nygren P (2021) A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer. Sci Rep 11(1):8981

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ (2017) Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int J Mol Sci 18(1):197

    Article  PubMed  PubMed Central  Google Scholar 

  • Martarelli D, Pompei P, Baldi C, Mazzoni G (2008) Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice. Cancer Chemother Pharmacol 61(5):809–817

    Article  CAS  PubMed  Google Scholar 

  • Meco D, Attinà G, Mastrangelo S, Navarra P, Ruggiero A (2023) Emerging perspectives on the antiparasitic mebendazole as a repurposed drug for the treatment of brain cancers. Int J mol Sci 24(2):1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Messaritakis J, Psychou P, Nicolaidou P, Karpathios T, Syriopoulou B, Fretzayas A, Krikos F, Matsaniotis N (1991) High mebendazole doses in pulmonary and hepatic hydatid disease. Arch Dis Child 66(4):532–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michiels M, Hendriks R, Heykants J, Van den Bossche H (1982) The pharmacokinetics of mebendazole and flubendazole in animals and man. Arch Int Pharmacodyn Ther 256(2):180–191

    CAS  PubMed  Google Scholar 

  • Mukhopadhyay T, Sasaki J-I, Ramesh R, Roth JA (2002) Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Can Res 8(9):2963–2969

    CAS  Google Scholar 

  • Nath J, Paul R, Ghosh SK, Paul J, Singha B, Debnath N (2020) Drug repurposing and relabeling for cancer therapy: emerging benzimidazole antihelminthics with potent anticancer effects. Life Sci 258:118189

    Article  CAS  PubMed  Google Scholar 

  • Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16(7):896–913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petersen JS, Baird SK (2021) Treatment of breast and colon cancer cell lines with anti-helmintic benzimidazoles mebendazole or albendazole results in selective apoptotic cell death. J Cancer Res Clin Oncol 147(10):2945–2953

    Article  CAS  PubMed  Google Scholar 

  • Pinto LC, Mesquita FP, Soares BM, da Silva EL, Puty B, de Oliveira EHC, Burbano RR, Montenegro RC (2019) Mebendazole induces apoptosis via C-MYC inactivation in malignant ascites cell line (AGP01). Toxicol in Vitro 60:305–312

    Article  CAS  PubMed  Google Scholar 

  • Reuter S, Jensen B, Buttenschoen K, Kratzer W, Kern P (2000) Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother 46(3):451–456

    Article  CAS  PubMed  Google Scholar 

  • Simbulan-Rosenthal CM, Dakshanamurthy S, Gaur A, Chen Y-S, Fang H-B, Abdussamad M, Zhou H, Zapas J, Calvert V, Petricoin EF (2017) The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma. Oncotarget 8(8):12576

    Article  PubMed  PubMed Central  Google Scholar 

  • Turabi KS, Deshmukh A, Paul S, Swami D, Siddiqui DS, Kumar U, Naikar S, Devarajan S, Basu S, Paul MK (2022) Drug repurposing—an emerging strategy in cancer therapeutics. Naunyn-Schmiedeberg's Arch Pharmacol, 1-20

  • Vasan N, Baselga J, Hyman DM (2019) A view on drug resistance in cancer. Nature 575(7782):299–309

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Williamson T, Bai R-Y, Staedtke V, Huso D, Riggins GJ (2016) Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model. Oncotarget 7(42):68571

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie Y-H, Chen Y-X, Fang J-Y (2020) Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 5(1):1–30

    Google Scholar 

  • Xu JX, Xiong W, Zeng Z, Tang Y, Wang YL, Xiao M, Li M, Li QS, Song GL, Kuang J (2017) Effect of ART1 on the proliferation and migration of mouse colon carcinoma CT26 cells in vivo. Mol Med Rep 15(3):1222–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zbakh H, Zubía E, de los Reyes C, Calderón-Montaño JM, López-Lázaro M, Motilva V (2020) Meroterpenoids from the brown alga Cystoseira usneoides as potential anti-inflammatory and lung anticancer agents. Marine Drugs 18(4):207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang F, Li Y, Zhang H, Huang E, Gao L, Luo W, Wei Q, Fan J, Song D, Liao J (2017) Anthelmintic mebendazole enhances cisplatin’s effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC). Oncotarget 8(8):12968

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Dratver MB, Yazal T, Dong K, Nguyen A, Yu G, Dao A, Dratver MB, Duhachek-Muggy S, Bhat K (2019) Mebendazole potentiates radiation therapy in triple-negative breast cancer. Int J Rad Oncol Biol Phys 103(1):195–207

    Article  CAS  Google Scholar 

  • Zhang Q-L, Lian D-D, Zhu MJ, Li XM, Lee JK, Yoon T-J, Lee J-H, JiangR-H Kim CD (2019) Antitumor effect of albendazole on cutaneous squamous cell carcinoma (SCC) cells. BioMed Res Int 2019:1–9

    Google Scholar 

Download references

Acknowledgements

This article was prepared from the Ph.D. thesis of Amin Aliabadi with the financial support of Shiraz University of Medical Sciences and Shiraz Cancer Research Institute.

The authors have no relevant financial or non-financial interests to disclose.

Funding

This study was financially supported by Shiraz University of Medical Sciences, Shiraz, Iran (grant number: 21962) and Shiraz Cancer Research Institute (grant number: ICR-100-500).

Author information

Author notes

  1. Mohammad Reza Panjehshahin and Nasrollah Erfani contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Amin Aliabadi, Azar Purkhosrow, Fatema Pirsalami & Mohammad Reza Panjehshahin

  2. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Reza Haghshenas, Razie Kiani & Nasrollah Erfani

  3. Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran

    Omid Koohi‑Hosseinabadi

  4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Reza Panjehshahin

  5. Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Nasrollah Erfani

Authors
  1. Amin Aliabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Reza Haghshenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Razie Kiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omid Koohi‑Hosseinabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Azar Purkhosrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fatema Pirsalami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammad Reza Panjehshahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nasrollah Erfani
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Nasrollah Erfani and Mohammad Reza Panjehshahin supervised the project.

Nasrollah Erfani, Mohammad Reza Panjehshahin, Mohammad Reza Haghshenas, Amin Aliabadi, and Razie Kiani conceived and planned the experiments.

Amin Aliabadi, Razie Kiani, Omid Koohi-Hosseinabadi, Azar Purkhosrow, and Fatema Pirsalami carried out the experiments.

Amin Aliabadi and Razie Kiani performed the analytic calculations (flow cytometry and statistical).

Nasrollah Erfani and Mohammad Reza Haghshenas verified the analytical methods.

Nasrollah Erfani, Mohammad Reza Panjehshahin, Mohammad Reza Haghshenas, Amin Aliabadi, and Razie Kiani discussed the results and contributed to the final manuscript.

Amin Aliabadi wrote the manuscript with support from Nasrollah Erfani, Mohammad Reza Panjehshahin, Mohammad Reza Haghshenas, and Razie Kiani.

The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Mohammad Reza Panjehshahin or Nasrollah Erfani.

Ethics declarations

Ethical approval

The research was authorized by the ethics committee of Shiraz University of Medical Sciences under code IR.SUMS.REC.1399.1264.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original version of this article was revised. The affiliation and affiliation links are now corrected.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aliabadi, A., Haghshenas, M.R., Kiani, R. et al. In vitro and in vivo anticancer activity of mebendazole in colon cancer: a promising drug repositioning. Naunyn-Schmiedeberg's Arch Pharmacol 397, 2379–2388 (2024). https://doi.org/10.1007/s00210-023-02722-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-023-02722-z

Keywords

Search

Navigation