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Involvement of reactive oxygen species in the anti-cancer activity of fenbendazole, a benzimidazole anthelmintic

Fenbendazole의 항암활성에서 활성산소종의 관련성

  • Han, Yong (Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Jeju National University) ;
  • Joo, Hong-Gu (Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Jeju National University)
  • 한용 (제주대학교 수의과대학 수의약리학실) ;
  • 주홍구 (제주대학교 수의과대학 수의약리학실)
  • Received : 2020.02.24
  • Accepted : 2020.05.20
  • Published : 2020.06.30

Abstract

Fenbendazole (FBZ) is a benzimidazole anthelmintic that has been widely used in treatments for gastrointestinal parasites including pinworms and roundworms in animals. Recently, some studies demonstrated that FBZ has anti-cancer effects related to disruption of microtubule polymerization. In this study, we investigated whether FBZ has anti-cancer activity in HL-60 cells, a human leukemia cell line, and assessed its relationship with the production of reactive oxygen species (ROS). FBZ treatment at 0.25-1 μM significantly decreased the metabolic activity of HL-60 cells. The mitochondrial membrane potential of FBZ-treated HL-60 cells decreased in a concentration-dependent manner. Apoptosis analysis using annexin V-FITC/propidium iodide staining demonstrated that 1 μM FBZ increased the percentages of cells in apoptosis and necrosis. In addition, Hoechst 33342 staining showed the presence of broken nuclei in HL-60 cells treated with 0.5 and 1 μM FBZ. To investigate the anti-cancer mechanism of FBZ, HL-60 cells were treated with FBZ in the absence or presence of N-acetyl cysteine (NAC), an inhibitor of ROS production. NAC significantly recovered the decreased metabolic activity of HL-60 induced by 0.5 and 1 μM FBZ treatments. This study provides evidence that FBZ has anti-cancer activity in HL-60 cells provided, in part, via ROS production.

Keywords

References

  1. Pritchett KR, Johnston NA. A review of treatments for the eradication of pinworm infections from laboratory rodent colonies. Contemp Top Lab Anim Sci 2002;41:36-46.
  2. Zajac AM. Developments in the treatment of gastrointestinal parasites of small animals. Vet Clin North Am Small Anim Pract 1993;23:671-681. https://doi.org/10.1016/S0195-5616(93)50312-1
  3. Muser RK, Paul JW. Safety of fenbendazole use in cattle. Mod Vet Pract 1984;65:371-374.
  4. Hayes RH, Oehme FW, Leipold H. Safety of fenbendazole in swine. Am J Vet Res 1983;44:1112-1116.
  5. Duan Q, Liu Y, Rockwell S. Fenbendazole as a potential anticancer drug. Anticancer Res 2013;33:355-362.
  6. Duan Q, Liu Y, Booth CJ, Rockwell S. Use of fenbendazolecontaining therapeutic diets for mice in experimental cancer therapy studies. J Am Assoc Lab Anim Sci 2012;51:224-230.
  7. Dogra N, Kumar A, Mukhopadhyay T. Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways. Sci Rep 2018;8:11926. https://doi.org/10.1038/s41598-018-30158-6
  8. Lai SR, Castello SA, Robinson AC, Koehler JW. In vitro antitubulin effects of mebendazole and fenbendazole on canine glioma cells. Vet Comp Oncol 2017;15:1445-1454. https://doi.org/10.1111/vco.12288
  9. Li R, Jia Z, Trush MA. Defining ROS in Biology and Medicine. React Oxyg Species (Apex) 2016;1:9-21.
  10. Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res 2009;66:121-127. https://doi.org/10.1203/PDR.0b013e3181a9eafb
  11. Zaidieh T, Smith JR, Ball KE, An Q. ROS as a novel indicator to predict anticancer drug efficacy. BMC Cancer 2019;19:1224. https://doi.org/10.1186/s12885-019-6438-y
  12. Ozben T. Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 2007;96:2181-2196. https://doi.org/10.1002/jps.20874
  13. Kim SY, Joo HG. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy. J Vet Sci 2015;16:145-150. https://doi.org/10.4142/jvs.2015.16.2.145
  14. Moon SY, Joo HG. Anti-inflammatory effects of 4,4'- diaminodiphenyl sulfone (dapsone) in lipopolysaccharidetreated spleen cells: selective inhibition of inflammation-related cytokines. Korean J Vet Res 2015;55:199-204. https://doi.org/10.14405/kjvr.2015.55.3.199
  15. Galadari S, Rahman A, Pallichankandy S, Thayyullathil F. Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic Biol Med 2017;104:144-164. https://doi.org/10.1016/j.freeradbiomed.2017.01.004
  16. Tafani M, Sansone L, Limana F, Arcangeli T, De Santis E, Polese M, Fini M, Russo MA. The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression. Oxid Med Cell Longev 2016;2016:3907147.
  17. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene 2003;22:7468-7485. https://doi.org/10.1038/sj.onc.1206948
  18. Ledoux S, Yang R, Friedlander G, Laouari D. Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res 2003;63:7284-7290.
  19. Hu Z, Zeng Q, Zhang B, Liu H, Wang W. Promotion of p53 expression and reactive oxidative stress production is involved in zerumbone-induced cisplatin sensitization of non-small cell lung cancer cells. Biochimie 2014;107 Pt B:257-262. https://doi.org/10.1016/j.biochi.2014.09.001
  20. Haugrud AB, Zhuang Y, Coppock JD, Miskimins WK. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat 2014;147:539-550. https://doi.org/10.1007/s10549-014-3128-y
  21. Sun SY. N-acetylcysteine, reactive oxygen species and beyond. Cancer Biol Ther 2010;9:109-110. https://doi.org/10.4161/cbt.9.2.10583
  22. Jeansonne DP, Koh GY, Zhang F, Kirk-Ballard H, Wolff L, Liu D, Eilertsen K, Liu Z. Paclitaxel-induced apoptosis is blocked by camptothecin in human breast and pancreatic cancer cells. Oncol Rep 2011;25:1473-1480.
  23. Ferguson PJ, Phillips JR, Selner M, Cass CE. Differential activity of vincristine and vinblastine against cultured cells. Cancer Res 1984;44:3307-3312.

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