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Translational Therapeutics

Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20

British Journal of Cancer volume 130, pages 1046–1058 (2024)Cite this article

Subjects

Abstract

Background

The repurposing of FDA-approved drugs for anti-cancer therapies is appealing due to their established safety profiles and pharmacokinetic properties and can be quickly moved into clinical trials. Cancer progression and resistance to conventional chemotherapy remain the key hurdles in improving the clinical management of colon cancer patients and associated mortality.

Methods

High-throughput screening (HTS) was performed using an annotated library of 1,600 FDA-approved drugs to identify drugs with strong anti-CRC properties. The candidate drug exhibiting most promising inhibitory effects in in-vitro studies was tested for its efficacy using in-vivo models of CRC progression and chemoresistance and patient derived organoids (PTDOs).

Results

Albendazole, an anti-helminth drug, demonstrated the strongest inhibitory effects on the tumorigenic potentials of CRC cells, xenograft tumor growth and organoids from mice. Also, albendazole sensitized the chemoresistant CRC cells to 5-fluorouracil (5-FU) and oxaliplatin suggesting potential to treat chemoresistant CRC. Mechanistically, Albendazole treatment modulated the expression of RNF20, to promote apoptosis in CRC cells by delaying the G2/M phase and suppressing anti-apoptotic-Bcl2 family transcription.

Conclusions

Albendazole, an FDA approved drug, carries strong therapeutic potential to treat colon cancers which are aggressive and potentially resistant to conventional chemotherapeutic agents. Our findings also lay the groundwork for further clinical testing.

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Fig. 1: Albendazole, an FDA-approved drug, inhibits cell survival, induces apoptosis, and exhibits antitumorigenic properties.
Fig. 2: Albendazole significantly inhibits tumor formation in xenograft CRC models.
Fig. 3: Albendazole remarkably inhibits the expression of RING-finger protein 20 (RNF20) and induces apoptosis by inhibiting the B-cell lymphoma (Bcl)-2 family anti-apoptotic markers.
Fig. 4: Albendazole inhibits the binding of RNF20 and Eg5, causing Eg5 degradation.
Fig. 5: Albendazole enhances chemosensitivity of colon cancer cells to 5-FU.
Fig. 6: Albendazole sensitizes chemo-resistant cells.

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Data availability

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

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Fatima I, Uppada JP, Chhonker YS, Gowrikumar S, Barman S, Roy S, et al. Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis. Biomed Pharmacother. 2023;159:114255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72:409–36.

    Article  PubMed  Google Scholar 

  4. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.

    Article  PubMed  Google Scholar 

  5. Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:372–401.

    Article  PubMed  Google Scholar 

  6. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Modest DP, Rivera F, Bachet JB, de Braud F, Pietrantonio F, Koukakis R, et al. Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials. Int J Cancer. 2019;145:576–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol. 2016;22:6876–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. El Zarif T, Yibirin M, De Oliveira-Gomes D, Machaalani M, Nawfal R, Bittar G, et al. Overcoming Therapy Resistance in Colon Cancer by Drug Repurposing. Cancers (Basel). 2022;14:2105.

    Article  CAS  PubMed  Google Scholar 

  10. Yeu Y, Yoon Y, Park S. Protein localization vector propagation: a method for improving the accuracy of drug repositioning. Mol Biosyst. 2015;11:2096–102.

    Article  CAS  PubMed  Google Scholar 

  11. Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012;11:191–200.

    Article  CAS  PubMed  Google Scholar 

  12. Horton J. Albendazole: a review of anthelmintic efficacy and safety in humans. Parasitology. 2000;121:S113–S132.

    Article  PubMed  Google Scholar 

  13. Conterno LO, Turchi MD, Correa I, Monteiro, de Barros Almeida RA. Anthelmintic drugs for treating ascariasis. Cochrane Database Syst Rev. 2020;4:CD010599.

    PubMed  Google Scholar 

  14. Zhou F, Du J, Wang J. Albendazole inhibits HIF-1alpha-dependent glycolysis and VEGF expression in non-small cell lung cancer cells. Mol Cell Biochem. 2017;428:171–8.

    Article  CAS  PubMed  Google Scholar 

  15. Pourgholami MH, Cai ZY, Wang L, Badar S, Links M, Morris DL. Inhibition of cell proliferation, vascular endothelial growth factor and tumor growth by albendazole. Cancer Invest. 2009;27:171–7.

    Article  CAS  PubMed  Google Scholar 

  16. Pourgholami MH, Cai ZY, Badar S, Wangoo K, Poruchynsky MS, Morris DL. Potent inhibition of tumoral hypoxia-inducible factor 1alpha by albendazole. BMC Cancer. 2010;10:143.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pourgholami MH, Khachigian LM, Fahmy RG, Badar S, Wang L, Chu SW, et al. Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis. Biochem Biophys Res Commun. 2010;397:729–34.

    Article  CAS  PubMed  Google Scholar 

  18. Wang LJ, Lee YC, Huang CH, Shi YJ, Chen YJ, Pei SN, et al. Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-alpha upregulation. Biochem Pharm. 2019;162:154–68.

    Article  CAS  PubMed  Google Scholar 

  19. Patel K, Doudican NA, Schiff PB, Orlow SJ. Albendazole sensitizes cancer cells to ionizing radiation. Radiat Oncol. 2011;6:160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jung YY, Baek SH, Ha IJ, Ahn KS. Regulation of apoptosis and autophagy by albendazole in human colon adenocarcinoma cells. Biochimie. 2022;198:155–66.

    Article  CAS  PubMed  Google Scholar 

  21. Pourgholami MH, Akhter J, Wang L, Lu Y, Morris DL. Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis. Cancer Chemother Pharm. 2005;55:425–32.

    Article  CAS  Google Scholar 

  22. Gowrikumar S, Primeaux M, Pravoverov K, Wu C, Szeglin BC, Sauve CG, et al. A claudin-based molecular signature identifies high-risk, chemoresistant colorectal cancer patients. Cells. 2021;10:2211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762–72.

    Article  CAS  PubMed  Google Scholar 

  24. Fatima I, Barman S, Uppada J, Chauhan S, Rauth S, Rachagani S, et al. MASTL regulates EGFR signaling to impact pancreatic cancer progression. Oncogene. 2021;40:5691–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. New-Aaron M, Koganti SS, Ganesan M, Kanika S, Kumar V, Wang W, et al. Hepatocyte-specific triggering of hepatic stellate cell profibrotic activation by apoptotic bodies: the role of hepatoma-derived growth factor, HIV, and ethanol. Int J Mol Sci. 2023;24:5346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fatima I, Saxena R, Kharkwal G, Hussain MK, Yadav N, Hajela K, et al. The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells. J Steroid Biochem Mol Biol. 2013;138:123–31.

    Article  CAS  PubMed  Google Scholar 

  27. Fatima I, El-Ayachi I, Taotao L, Lillo MA, Krutilina RI, Seagroves TN, et al. The natural compound Jatrophone interferes with Wnt/beta-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. PLoS One. 2017;12:e0189864.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kumar B, Ahmad R, Sharma S, Gowrikumar S, Primeaux M, Rana S, et al. PIK3C3 inhibition promotes sensitivity to colon cancer therapy by inhibiting cancer stem cells. Cancers (Basel). 2021;13:2168.

    Article  CAS  PubMed  Google Scholar 

  29. Luzak B, Siarkiewicz P, Boncler M. An evaluation of a new high-sensitivity PrestoBlue assay for measuring cell viability and drug cytotoxicity using EA.hy926 endothelial cells. Toxicol Vitr. 2022;83:105407.

    Article  CAS  Google Scholar 

  30. Kaemmerer E, Klaus C, Jeon MK, Gassler N. Molecular classification of colorectal carcinomas: the genotype-to-phenotype relation. World J Gastroenterol. 2013;19:8163–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhu L, Yang Q, Hu R, Li Y, Peng Y, Liu H, et al. Novel therapeutic strategy for melanoma based on albendazole and the CDK4/6 inhibitor palbociclib. Sci Rep. 2022;12:5706.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Petersen J, Baird SK. 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. 2021;147:2945–53.

    Article  CAS  PubMed  Google Scholar 

  33. Fatima I, El-Ayachi I, Taotao L, Angeles Lillo M, Krutilina RI, Seagroves TN, et al. Correction: The natural compound Jatrophone interferes with Wnt/beta-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer. PLoS One. 2018;13:e0197796.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Xia W, Spector S, Hardy L, Zhao S, Saluk A, Alemane L, et al. Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine. Proc Natl Acad Sci USA. 2000;97:7494–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hulkower KI, Herber RL. Cell migration and invasion assays as tools for drug discovery. Pharmaceutics. 2011;3:107–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kowtharapu BS, Murin R, Junemann AGM, Stachs O. Role of corneal stromal cells on epithelial cell function during wound healing. Int J Mol Sci. 2018;19:464.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Fatima I, El-Ayachi I, Playa HC, Alva-Ornelas JA, Khalid AB, Kuenzinger WL, et al. Simultaneous multi-organ metastases from chemo-resistant triple-negative breast cancer are prevented by interfering with WNT-signaling. Cancers (Basel). 2019;11:2039.

    Article  CAS  PubMed  Google Scholar 

  38. Ehteda A, Galettis P, Pillai K, Morris DL. Combination of albendazole and 2-methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice. BMC Cancer. 2013;13:86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Will Castro L, Pieters W, Alemdehy MF, Aslam MA, Buoninfante OA, Raaijmakers JA, et al. The widely used antihelmintic drug albendazole is a potent inducer of loss of heterozygosity. Front Pharm. 2021;12:596535.

    Article  Google Scholar 

  40. Duan Y, Huo D, Gao J, Wu H, Ye Z, Liu Z, et al. Corrigendum: Ubiquitin ligase RNF20/40 facilitates spindle assembly and promotes breast carcinogenesis through stabilizing motor protein Eg5. Nat Commun. 2016;7:13462.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pavri R, Zhu B, Li G, Trojer P, Mandal S, Shilatifard A, et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell. 2006;125:703–17.

    Article  CAS  PubMed  Google Scholar 

  42. Schulze JM, Jackson J, Nakanishi S, Gardner JM, Hentrich T, Haug J, et al. Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation. Mol Cell. 2009;35:626–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Parang B, Barrett CW, Williams CS. AOM/DSS model of colitis-associated cancer. Methods Mol Biol. 2016;1422:297–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–4.

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Schneider D, Chua RL, Molitor N, Hamdan FH, Rettenmeier EM, Prokakis E, et al. The E3 ubiquitin ligase RNF40 suppresses apoptosis in colorectal cancer cells. Clin Epigenetics. 2019;11:98.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, et al. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005;20:601–11.

    Article  CAS  PubMed  Google Scholar 

  48. Saijo T, Ishii G, Ochiai A, Yoh K, Goto K, Nagai K, et al. Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. Lung Cancer. 2006;54:217–25.

    Article  PubMed  Google Scholar 

  49. Yan GR, Zou FY, Dang BL, Zhang Y, Yu G, Liu X, et al. Genistein-induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study. Proteomics. 2012;12:2391–9.

    Article  CAS  PubMed  Google Scholar 

  50. Jin Q, Dai Y, Wang Y, Zhang S, Liu G. High kinesin family member 11 expression predicts poor prognosis in patients with clear cell renal cell carcinoma. J Clin Pathol. 2019;72:354–62.

    Article  CAS  PubMed  Google Scholar 

  51. Kim M, Jeong HJ, Ju HM, Song JY, Jang SJ, Choi J. Overexpression of the NEK9-EG5 axis is a novel metastatic marker in pathologic stage T3 colon cancer. Sci Rep. 2023;13:342.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun L, Lu J, Niu Z, Ding K, Bi D, Liu S, et al. A potent chemotherapeutic strategy with Eg5 inhibitor against gemcitabine resistant bladder cancer. PLoS One. 2015;10:e0144484.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001;2:195–201.

    Article  CAS  PubMed  Google Scholar 

  54. Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;8:57–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938–47.

    Article  PubMed  Google Scholar 

  56. Pardini B, Kumar R, Naccarati A, Novotny J, Prasad RB, Forsti A, et al. 5-Fluorouracil-based chemotherapy for colorectal cancer and MTHFR/MTRR genotypes. Br J Clin Pharm. 2011;72:162–3.

    Article  CAS  Google Scholar 

  57. Denise C, Paoli P, Calvani M, Taddei ML, Giannoni E, Kopetz S, et al. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget. 2015;6:41706–21.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sanchez-Diez M, Alegria-Aravena N, Lopez-Montes M, Quiroz-Troncoso J, Gonzalez-Martos R, Menendez-Rey A, et al. Implication of different tumor biomarkers in drug resistance and invasiveness in primary and metastatic colorectal cancer cell lines. Biomedicines. 2022;10:1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101:14228–33.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92.

    Article  CAS  PubMed  Google Scholar 

  61. Pantziarka P, Verbaanderd C, Sukhatme V, Rica Capistrano I, Crispino S, Gyawali B, et al. ReDO_DB: the repurposing drugs in oncology database. Ecancermedicalscience. 2018;12:886.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004;3:673–83.

    Article  CAS  PubMed  Google Scholar 

  63. Lacey E. Mode of action of benzimidazoles. Parasitol Today. 1990;6:112–5.

    Article  CAS  PubMed  Google Scholar 

  64. Pourgholami MH, Woon L, Almajd R, Akhter J, Bowery P, Morris DL. In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer Lett. 2001;165:43–49.

    Article  CAS  PubMed  Google Scholar 

  65. Pourgholami MH, Yan Cai Z, Lu Y, Wang L, Morris DL. Albendazole: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation in OVCAR-3 tumor-bearing nude mice. Clin Cancer Res. 2006;12:1928–35.

    Article  PubMed  Google Scholar 

  66. Laudisi F, Maronek M, Di Grazia A, Monteleone G, Stolfi C. Repositioning of anthelmintic drugs for the treatment of cancers of the digestive system. Int J Mol Sci. 2020;21:4957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang P, Zhang Y, Liu K, Liu B, Xu W, Gao J, et al. Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Cell Prolif. 2019;52:e12543.

    Article  PubMed  Google Scholar 

  68. Shangguan F, Liu Y, Ma L, Qu G, Lv Q, An J, et al. Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics. J Cancer. 2020;11:3454–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen D, Sun X, Zhang X, Cao J. Targeting mitochondria by anthelmintic drug atovaquone sensitizes renal cell carcinoma to chemotherapy and immunotherapy. J Biochem Mol Toxicol. 2018;32:e22195.

    Article  PubMed  Google Scholar 

  70. Furst R, Vollmar AM. A new perspective on old drugs: non-mitotic actions of tubulin-binding drugs play a major role in cancer treatment. Pharmazie. 2013;68:478–83.

    CAS  PubMed  Google Scholar 

  71. Risinger AL, Dybdal-Hargreaves NF, Mooberry SL. Breast cancer cell lines exhibit differential sensitivities to microtubule-targeting drugs independent of doubling time. Anticancer Res. 2015;35:5845–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bates DJ, Danilov AV, Lowrey CH, Eastman A. Vinblastine rapidly induces NOXA and acutely sensitizes primary chronic lymphocytic leukemia cells to ABT-737. Mol Cancer Ther. 2013;12:1504–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chu B, Liu F, Li L, Ding C, Chen K, Sun Q, et al. A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells. Cell Death Dis. 2015;6:e1686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Haschka MD, Soratroi C, Kirschnek S, Hacker G, Hilbe R, Geley S, et al. The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun. 2015;6:6891.

    Article  ADS  CAS  PubMed  Google Scholar 

  75. Ghasemi F, Black M, Vizeacoumar F, Pinto N, Ruicci KM, Le C, et al. Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer. Oncotarget. 2017;8:71512–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Liu H, Sun H, Zhang B, Liu S, Deng S, Weng Z, et al. (18)F-FDG PET imaging for monitoring the early anti-tumor effect of albendazole on triple-negative breast cancer. Breast Cancer. 2020;27:372–80.

    Article  PubMed  Google Scholar 

  77. Liu S, Liu H, Sun H, Deng S, Yue L, Weng Z, et al. (cRGD)2 peptides modified nanoparticles increase tumor-targeting therapeutic effects by co-delivery of albendazole and iodine-131. Anticancer Drugs. 2022;33:19–29.

    Article  CAS  PubMed  Google Scholar 

  78. Chen H, Weng Z, Xu C. Albendazole suppresses cell proliferation and migration and induces apoptosis in human pancreatic cancer cells. Anticancer Drugs. 2020;31:431–9.

    Article  CAS  PubMed  Google Scholar 

  79. Sethi G, Shanmugam MK, Arfuso F, Kumar AP. Role of RNF20 in cancer development and progression—a comprehensive review. Biosci Rep. 2018;38.

  80. Wood A, Krogan NJ, Dover J, Schneider J, Heidt J, Boateng MA, et al. Bre1, an E3 ubiquitin ligase required for recruitment and substrate selection of Rad6 at a promoter. Mol Cell. 2003;11:267–74.

    Article  CAS  PubMed  Google Scholar 

  81. Hwang WW, Venkatasubrahmanyam S, Ianculescu AG, Tong A, Boone C, Madhani HD. A conserved RING finger protein required for histone H2B monoubiquitination and cell size control. Mol Cell. 2003;11:261–6.

    Article  CAS  PubMed  Google Scholar 

  82. So CC, Ramachandran S, Martin A. E3 Ubiquitin Ligases RNF20 and RNF40 are required for double-stranded break (DSB) repair: evidence for monoubiquitination of histone H2B Lysine 120 as a novel axis of DSB signaling and repair. Mol Cell Biol. 2019;39.

  83. Moyal L, Lerenthal Y, Gana-Weisz M, Mass G, So S, Wang SY, et al. Requirement of ATM-dependent monoubiquitylation of histone H2B for timely repair of DNA double-strand breaks. Mol Cell. 2011;41:529–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wegwitz F, Prokakis E, Pejkovska A, Kosinsky RL, Glatzel M, Pantel K, et al. The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis. Cell Death Dis. 2020;11:873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chernikova SB, Razorenova OV, Higgins JP, Sishc BJ, Nicolau M, Dorth JA, et al. Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability. Cancer Res. 2012;72:2111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jaaskelainen T, Makkonen H, Visakorpi T, Kim J, Roeder RG, Palvimo JJ. Histone H2B ubiquitin ligases RNF20 and RNF40 in androgen signaling and prostate cancer cell growth. Mol Cell Endocrinol. 2012;350:87–98.

    Article  CAS  PubMed  Google Scholar 

  87. Wang E, Kawaoka S, Yu M, Shi J, Ni T, Yang W, et al. Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Proc Natl Acad Sci USA. 2013;110:3901–6.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sawin KE, LeGuellec K, Philippe M, Mitchison TJ. Mitotic spindle organization by a plus-end-directed microtubule motor. Nature. 1992;359:540–3.

    Article  ADS  CAS  PubMed  Google Scholar 

  89. She ZY, Zhong N, Yu KW, Xiao Y, Wei YL, Lin Y, et al. Kinesin-5 Eg5 is essential for spindle assembly and chromosome alignment of mouse spermatocytes. Cell Div. 2020;15:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kapoor TM, Mitchison TJ. Eg5 is static in bipolar spindles relative to tubulin: evidence for a static spindle matrix. J Cell Biol. 2001;154:1125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Garcia-Saez I, Skoufias DA. Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance. Biochem Pharm. 2021;184:114364.

    Article  CAS  PubMed  Google Scholar 

  92. Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol. 2000;150:975–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yang L, Jiang C, Liu F, You QD, Wu WT. Cloning, enzyme characterization of recombinant human Eg5 and the development of a new inhibitor. Biol Pharm Bull. 2008;31:1397–402.

    Article  CAS  PubMed  Google Scholar 

  94. Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, et al. K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res. 2009;69:3901–9.

    Article  CAS  PubMed  Google Scholar 

  95. Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8:38022–43.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by BX002086 (VA merit), CA250383 (NIH/NCI), CA216746 (NIH/NCI) and Nebraska Research Initiative (NRI) to P.D and DK124095 and BX002761 (VA merit) to ABS. We also acknowledge NCI Cancer Center Support Grant P30 CA36727, NIH-1P50 CA 127297-01A2 for tissue arrays obtained. We also acknowledge Dr. Lynette M Smith, biostatistician, for analyzing the IC50 experiment data.

Funding

This study was supported by BX002086 (VA merit), CA250383 (NIH/NCI), CA216746 (NIH/NCI) and Nebraska Research Initiative (NRI) to P.D and DK124095 and BX002761 (VA merit) to ABS. We also acknowledge NCI Cancer Center Support Grant P30 CA36727, NIH-1P50 CA 127297-01A2 for tissue arrays obtained.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Iram Fatima, Rizwan Ahmad, Susmita Barman, Saiprasad Gowrikumar, Kristina Pravoverov, Mark Primeaux, Amar B. Singh & Punita Dhawan

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Kurt W. Fisher

  3. Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Amar B. Singh & Punita Dhawan

  4. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    Amar B. Singh & Punita Dhawan

Authors
  1. Iram Fatima
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  2. Rizwan Ahmad
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  3. Susmita Barman
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  4. Saiprasad Gowrikumar
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  5. Kristina Pravoverov
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  6. Mark Primeaux
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  7. Kurt W. Fisher
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  8. Amar B. Singh
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  9. Punita Dhawan
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Contributions

PD and IF conceived the study and participated in the study design, performance, coordination, and manuscript writing. IF, RA, SB, SG, KP, MP and KWF carried out the assays and analysis. ABS revised the manuscript. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Punita Dhawan.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were conducted with the approval of the UNMC Institutional Animal Care and Use Committee (IACUC; protocol #16-021-04FC). There is no human study.

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Fatima, I., Ahmad, R., Barman, S. et al. Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20. Br J Cancer 130, 1046–1058 (2024). https://doi.org/10.1038/s41416-023-02570-x

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  • DOI: https://doi.org/10.1038/s41416-023-02570-x

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