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.

中文翻译：

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伊维菌素在临床上可行的浓度下的抗肿瘤作用支持其作为重新定位的癌症药物的临床开发。

目的

伊维菌素是一种抗寄生虫药物，在临床前研究中表现出抗肿瘤作用，因此目前正被重新定位用于癌症治疗。但是，在临床前工作中，其使用剂量存在分歧。因此，本研究的目的是确定在临床上可行的药物浓度下是否可观察到伊维菌素的抗肿瘤作用。

方法

用5μM伊维菌素处理了28个恶性细胞系。评估了细胞活力，克隆形成力，细胞周期，细胞死亡以及与常见细胞毒性药物的药理相互作用，以及其对富含干细胞的人群的影响。还评估了伊维菌素的体内抗肿瘤作用。

结果

乳房MDA-MB-231，MDA-MB-468和MCF-7和卵巢SKOV-3是对伊维菌素最敏感的癌细胞系。相反，前列腺癌细胞系DU145对其使用最有抵抗力。在最敏感的细胞中，伊维菌素诱导的细胞周期停在G ₀ –G ₁相，并调节与细胞周期控制有关的蛋白质。此外，伊维菌素与多西他赛，环磷酰胺和他莫昔芬具有协同作用。与亲本相比，伊维菌素在富含干细胞的人群中降低了细胞活力和集落形成能力。最后，在荷瘤小鼠中，伊维菌素成功降低了肿瘤的大小和重量。

结论

我们关于伊维菌素抗肿瘤作用的结果支持其临床测试。