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Antitumor effects of ivermectin at clinically feasible concentrations support its clinical development as a repositioned cancer drug

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Abstract

Purpose

Ivermectin is an antiparasitic drug that exhibits antitumor effects in preclinical studies, and as such is currently being repositioned for cancer treatment. However, divergences exist regarding its employed doses in preclinical works. Therefore, the aim of this study was to determine whether the antitumor effects of ivermectin are observable at clinically feasible drug concentrations.

Methods

Twenty-eight malignant cell lines were treated with 5 μM ivermectin. Cell viability, clonogenicity, cell cycle, cell death and pharmacological interaction with common cytotoxic drugs were assessed, as well as the consequences of its use on stem cell-enriched populations. The antitumor in vivo effects of ivermectin were also evaluated.

Results

The breast MDA-MB-231, MDA-MB-468, and MCF-7, and the ovarian SKOV-3, were the most sensitive cancer cell lines to ivermectin. Conversely, the prostate cancer cell line DU145 was the most resistant to its use. In the most sensitive cells, ivermectin induced cell cycle arrest at G0–G1 phase, with modulation of proteins associated with cell cycle control. Furthermore, ivermectin was synergistic with docetaxel, cyclophosphamide and tamoxifen. Ivermectin reduced both cell viability and colony formation capacity in the stem cell-enriched population as compared with the parental one. Finally, in tumor-bearing mice ivermectin successfully reduced both tumor size and weight.

Conclusion

Our results on the antitumor effects of ivermectin support its clinical testing.

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References

  1. Omura S, Crump A (2004) The life and times of ivermectin—a success story. Nat Rev Microbiol 2(12):984–989. https://doi.org/10.1038/nrmicro1048

    Article  CAS  PubMed  Google Scholar 

  2. Omura S (2008) Ivermectin: 25 years and still going strong. Int J Antimicrob Agents 31(2):91–98. https://doi.org/10.1016/j.ijantimicag.2007.08.023

    Article  CAS  PubMed  Google Scholar 

  3. Chabala JC, Mrozik H, Tolman RL, Eskola P, Lusi A, Peterson LH, Woods MF, Fisher MH, Campbell WC, Egerton JR, Ostlind DA (1980) Ivermectin, a new broad-spectrum antiparasitic agent. J Med Chem 23(10):1134–1136. https://doi.org/10.1021/jm00184a014

    Article  CAS  PubMed  Google Scholar 

  4. Goa KL, McTavish D, Clissold SP (1991) Ivermectin. A review of its antifilarial activity, pharmacokinetic properties and clinical efficacy in onchocerciasis. Drugs 42(4):640–658. https://doi.org/10.2165/00003495-199142040-00007

    Article  CAS  PubMed  Google Scholar 

  5. Kumaraswami V, Ottesen EA, Vijayasekaran V, Devi U, Swaminathan M, Aziz MA, Sarma GR, Prabhakar R, Tripathy SP (1988) Ivermectin for the treatment of Wuchereria bancrofti filariasis. Efficacy and adverse reactions. JAMA 259(21):3150–3153

    Article  CAS  Google Scholar 

  6. Marti H, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Ameir JS, Hatz C (1996) A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg 55(5):477–481. https://doi.org/10.4269/ajtmh.1996.55.477

    Article  CAS  PubMed  Google Scholar 

  7. Whitworth JA, Morgan D, Maude GH, McNicholas AM, Taylor DW (1991) A field study of the effect of ivermectin on intestinal helminths in man. Trans R Soc Trop Med Hyg 85(2):232–234. https://doi.org/10.1016/0035-9203(91)90037-y

    Article  CAS  PubMed  Google Scholar 

  8. Wolstenholme AJ (2012) Glutamate-gated chloride channels. J Biol Chem 287(48):40232–40238. https://doi.org/10.1074/jbc.R112.406280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dominguez-Gomez G, Chavez-Blanco A, Medina-Franco JL, Saldivar-Gonzalez F, Flores-Torrontegui Y, Juarez M, Diaz-Chavez J, Gonzalez-Fierro A, Duenas-Gonzalez A (2018) Ivermectin as an inhibitor of cancer stem-like cells. Mol Med Rep 17(2):3397–3403. https://doi.org/10.3892/mmr.2017.8231

    Article  CAS  PubMed  Google Scholar 

  10. Juarez M, Schcolnik-Cabrera A, Duenas-Gonzalez A (2018) The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res 8(2):317–331

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Didier A, Loor F (1996) The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor. Anticancer Drugs 7(7):745–751. https://doi.org/10.1097/00001813-199609000-00005

    Article  CAS  PubMed  Google Scholar 

  12. Liu Y, Fang S, Sun Q, Liu B (2016) Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun 480(3):415–421. https://doi.org/10.1016/j.bbrc.2016.10.064

    Article  CAS  PubMed  Google Scholar 

  13. Melotti A, Mas C, Kuciak M, Lorente-Trigos A, Borges I, Ruiz i Altaba A (2014) The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med 6(10):1263–1278. https://doi.org/10.15252/emmm.201404084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hashimoto H, Messerli SM, Sudo T, Maruta H (2009) Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther 3(6):243–246

    CAS  PubMed  Google Scholar 

  15. Dou Q, Chen HN, Wang K, Yuan K, Lei Y, Li K, Lan J, Chen Y, Huang Z, Xie N, Zhang L, Xiang R, Nice EC, Wei Y, Huang C (2016) Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. Cancer Res 76(15):4457–4469. https://doi.org/10.1158/0008-5472.CAN-15-2887

    Article  CAS  PubMed  Google Scholar 

  16. Kwon YJ, Petrie K, Leibovitch BA, Zeng L, Mezei M, Howell L, Gil V, Christova R, Bansal N, Yang S, Sharma R, Ariztia EV, Frankum J, Brough R, Sbirkov Y, Ashworth A, Lord CJ, Zelent A, Farias E, Zhou MM, Waxman S (2015) Selective Inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer. Mol Cancer Ther 14(8):1824–1836. https://doi.org/10.1158/1535-7163.MCT-14-0980-T

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yin J, Park G, Lee JE, Choi EY, Park JY, Kim TH, Park N, Jin X, Jung JE, Shin D, Hong JH, Kim H, Yoo H, Lee SH, Kim YJ, Park JB, Kim JH (2015) DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain 138(Pt 9):2553–2570. https://doi.org/10.1093/brain/awv167

    Article  PubMed  Google Scholar 

  18. Sharmeen S, Skrtic M, Sukhai MA, Hurren R, Gronda M, Wang X, Fonseca SB, Sun H, Wood TE, Ward R, Minden MD, Batey RA, Datti A, Wrana J, Kelley SO, Schimmer AD (2010) The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood 116(18):3593–3603. https://doi.org/10.1182/blood-2010-01-262675

    Article  CAS  PubMed  Google Scholar 

  19. Draganov D, Gopalakrishna-Pillai S, Chen YR, Zuckerman N, Moeller S, Wang C, Ann D, Lee PP (2015) Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep 5:16222. https://doi.org/10.1038/srep16222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Norenberg W, Sobottka H, Hempel C, Plotz T, Fischer W, Schmalzing G, Schaefer M (2012) Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors. Br J Pharmacol 167(1):48–66. https://doi.org/10.1111/j.1476-5381.2012.01987.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC (2002) Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 42(10):1122–1133. https://doi.org/10.1177/009127002401382731

    Article  CAS  PubMed  Google Scholar 

  22. Soule HD, Maloney TM, Wolman SR, Peterson WD Jr, Brenz R, McGrath CM, Russo J, Pauley RJ, Jones RF, Brooks SC (1990) Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 50(18):6075–6086

    CAS  PubMed  Google Scholar 

  23. Matthews H, Deakin J, Rajab M, IdrisUsman M, Nirmalan NJ (2017) Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. PLoS ONE 12(3):e0173303. https://doi.org/10.1371/journal.pone.0173303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wei Z, Lv S, Wang Y, Sun M, Chi G, Guo J, Song P, Fu X, Zhang S, Li Y (2016) Biological characteristics of side population cells in a self-established human ovarian cancer cell line. Oncol Lett 12(1):41–48. https://doi.org/10.3892/ol.2016.4565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koshkin V, Ailles LE, Liu G, Krylov SN (2017) Preservation of the 3D phenotype upon dispersal of cultured cell spheroids into monolayer cultures. J Cell Biochem 118(1):154–162. https://doi.org/10.1002/jcb.25621

    Article  CAS  PubMed  Google Scholar 

  26. Oda M, Saitoh H, Kobayashi M, Aungst BJ (2004) Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs. Int J Pharm 280(1–2):95–102. https://doi.org/10.1016/j.ijpharm.2004.05.003

    Article  CAS  PubMed  Google Scholar 

  27. Reagan–Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22(3):659–661. https://doi.org/10.1096/fj.07-9574LSF

    Article  CAS  PubMed  Google Scholar 

  28. Zhang P, Zhang Y, Liu K, Liu B, Xu W, Gao J, Ding L, Tao L (2019) Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Cell Prolif 52(2):e12543. https://doi.org/10.1111/cpr.12543

    Article  CAS  PubMed  Google Scholar 

  29. Song D, Liang H, Qu B, Li Y, Liu J, Zhang Y, Li L, Hu L, Zhang X, Gao A (2019) Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo. J Cell Biochem 120(1):622–633. https://doi.org/10.1002/jcb.27420

    Article  CAS  PubMed  Google Scholar 

  30. Baltus GA, Kowalski MP, Tutter AV, Kadam S (2009) A positive regulatory role for the mSin3A-HDAC complex in pluripotency through Nanog and Sox2. J Biol Chem 284(11):6998–7006. https://doi.org/10.1074/jbc.M807670200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang L, Wang P, Sun YJ, Wu YJ (2019) Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. J Exp Clin Cancer Res 38(1):265. https://doi.org/10.1186/s13046-019-1251-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kirk J, Syed SK, Harris AL, Jarman M, Roufogalis BD, Stratford IJ, Carmichael J (1994) Reversal of P-glycoprotein-mediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives. Biochem Pharmacol 48(2):277–285. https://doi.org/10.1016/0006-2952(94)90098-1

    Article  CAS  PubMed  Google Scholar 

  33. Holm C, Rayala S, Jirstrom K, Stal O, Kumar R, Landberg G (2006) Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J Natl Cancer Inst 98(10):671–680. https://doi.org/10.1093/jnci/djj185

    Article  CAS  PubMed  Google Scholar 

  34. Jaferian S, Soleymaninejad M, Daraee H (2018) Verapamil (VER) enhances the cytotoxic effects of docetaxel and vinblastine combined therapy against non-small cell lung cancer cell lines. Drug Res 68(3):146–152. https://doi.org/10.1055/s-0043-117895

    Article  CAS  Google Scholar 

  35. Brayboy LM, Oulhen N, Witmyer J, Robins J, Carson S, Wessel GM (2013) Multidrug-resistant transport activity protects oocytes from chemotherapeutic agents and changes during oocyte maturation. Fertil Steril 100(5):1428–1435. https://doi.org/10.1016/j.fertnstert.2013.07.002

    Article  CAS  PubMed  Google Scholar 

  36. Toledo-Guzman ME, Hernandez MI, Gomez-Gallegos AA, Ortiz-Sanchez E (2019) ALDH as a stem cell marker in solid tumors. Curr Stem Cell Res Ther 14(5):375–388. https://doi.org/10.2174/1574888X13666180810120012

    Article  PubMed  Google Scholar 

  37. Emadi A, Jones RJ, Brodsky RA (2009) Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6(11):638–647. https://doi.org/10.1038/nrclinonc.2009.146

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Rocío Morales-Bárcenas for her technical support with the use of the flow cytometer at the National Institute of Oncology (Mexico City, Mexico). This work was supported by the National Council of Science and Technology (CONACYT) scholarship # 288278, provided to MJ. MJ is a student belonging to the Programa de Ciencias Bioquímicas, and ASC to the Plan de Estudios Combinados en Medicina, both from the UNAM.

Funding

This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Instituto Nacional de Cancerologia, Mexico City, Mexico

    Mandy Juarez, Alejandro Schcolnik-Cabrera, Guadalupe Dominguez-Gomez, Alma Chavez-Blanco, Jose Diaz-Chavez & Alfonso Duenas-Gonzalez

  2. Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, San Fernando 22, Tlalpan, 14080, Mexico City, Mexico

    Alfonso Duenas-Gonzalez

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  1. Mandy Juarez
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Correspondence to Alfonso Duenas-Gonzalez.

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All animal experiments were approved and conducted under the guidelines of the Bioethical and Scientific committees of the National Institute of Oncology (protocol numbers CEI/1145/17 and 017/016/IBI, respectively), in Mexico City, Mexico.

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280_2020_4041_MOESM3_ESM.tiff

Supplementary file3 (TIFF 1853 kb) Fluorescence-activated cell sorting of the SKOV-3, MCF-7 and MDA-MB-468 cell lines. The parental cell line SKOV-3, MCF-7 and MDA-MB-468 had a cancer stem-like population in the range of 0.3% (A), 1.9% (C) and 5.5% (E), respectively, which increased to 30.8% (B), 34.8% (D), and 12.8% (F) after the sorting, respectively

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Juarez, M., Schcolnik-Cabrera, A., Dominguez-Gomez, G. et al. Antitumor effects of ivermectin at clinically feasible concentrations support its clinical development as a repositioned cancer drug. Cancer Chemother Pharmacol 85, 1153–1163 (2020). https://doi.org/10.1007/s00280-020-04041-z

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  • DOI: https://doi.org/10.1007/s00280-020-04041-z

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