Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology https://doi.org/10.1007/s00280-020-04041-z ORIGINAL ARTICLE Antitumor efects of ivermectin at clinically feasible concentrations support its clinical development as a repositioned cancer drug Mandy Juarez 1  · Alejandro Schcolnik‑Cabrera 1  · Guadalupe Dominguez‑Gomez 1  · Alma Chavez‑Blanco 1  · Jose Diaz‑Chavez 1  · Alfonso Duenas‑Gonzalez 1,2 Received: 14 October 2019 / Accepted: 7 February 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Purpose Ivermectin is an antiparasitic drug that exhibits antitumor efects 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 efects 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 efects 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 G 0 –G 1 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 efects of ivermectin support its clinical testing. Keywords Ivermectin · Cancer · Cancer stem cells · Drug repurposing Introduction Avermectins are a complex of 16-membered macrocyclic lactones produced from soil fermentation of the actinomy- cete Streptomyces avermitilis [1, 2]. Eight avermectin com- pounds exist (A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b), and among them, the mixture of 80% B1a and 20% B1b has the highest antiparasitic activity and safety [3]. Such mix compound is known as ivermectin [3]. Ivermectin is a broad- spectrum antiparasitic agent with human therapeutic dose rang between 0.1 and 0.4 mg/kg [4–7]. As an antiparasitic, ivermectin prevents the closure of glutamate-gated chloride ion channels, leading to plasma membrane hyperpolariza- tion, which paralyzes pharyngeal and somatic muscles of the parasite, leading to its death [8]. Ivermectin is a drug candidate for repurposing as an anticancer drug [9]. As such, it is important to determine whether its antitumor efects in vitro can be achieved at pharmacological doses. The therapeutic doses as an antipar- asitic compound in human ranges between 0.1 and 0.4 mg/ kg, resulting in an AUC of 1444 µg/h/mL, which translates into 1.65 µM using the calculator found in https://www. tocris.com/resources/molarity-calculator, which considers the molecular weight of ivermectin of 875.1 g/mol, a volume of 1 mL, and the mass of 1.444 µg/h/mL. Nevertheless, stud- ies showing the in vitro antitumor efects of ivermectin use this drug at concentrations up to 100 µM, which could not Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04041-z) contains supplementary material, which is available to authorized users. * Alfonso Duenas-Gonzalez alfonso_duenasg@yahoo.com 1 Instituto Nacional de Cancerologia, Mexico City, Mexico 2 Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, San Fernando 22, Tlalpan, 14080 Mexico City, Mexico