Ivermectin inhibits canine mammary tumor growth by regulating cell cycle progression and WNT signaling

Abstract

Background Mammary gland tumor is the most common spontaneous tumor in intact female dogs, and its poor prognosis remains a clinical challenge. Ivermectin, a well-known anti-parasitic agent, has been implicated as a potential anticancer agent in various types of human cancer. However, there are no reports evaluating the antitumor effects of ivermectin in canine mammary tumor. Here, we investigated whether ivermectin was able to inhibit canine mammary tumor development and explored the related mechanisms. Results Ivermectin inhibited the growth of canine mammary tumor cell lines in a dose- and time-dependent manner. The antitumor effects induced by ivermectin were associated with cell cycle arrest at G1 phase via down-regulation of CDK4 and cyclin D1 expression, with no significant induction of apoptosis. Furthermore, significantly reduced β-catenin nuclear translocation was observed after treatment with ivermectin, resulting in the inactivation of WNT signaling. Consistent with the results in vitro, a significant suppression of tumor growth by ivermectin was observed in canine mammary tumor xenografts. Conclusion Ivermectin, as a promising anti-cancer agent, inhibits the growth of canine mammary tumor by regulating cell cycle progression and WNT signaling. Electronic supplementary material The online version of this article (10.1186/s12917-019-2026-2) contains supplementary material, which is available to authorized users.

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

“…This pathway regulates cell proliferation and metastasis. The antitumor effect of ivermectin in human colon cancer and lung carcinoma xenograft is dependent on WNT-TCF signaling pathway, it is effective if the cancer is WNT-TCF-dependent and ineffective if it is not [118]. The potency of ivermectin as an anticancer in a glioma xenograft is also observed by inhibiting DEAD-vox RNA helicase DDX23 [119].…”

SILAC quantitative proteomics analysis of ivermectin‐related proteomic profiling and molecular network alterations in human ovarian cancer cells

“…CCND1 (changed ratio = 0.40) in the cell‐cycle pathway acted as a regulatory subunit of CDK4 or CDK6, whose activity was required for cell cycle G1/S transition. Ivermectin could inhibit the growth of mammary tumor cells in a dose‐ and time‐dependent manner by controlling cell‐cycle arrest at G1 phase via down‐regulation of CDK4 and cyclin D1 expressions 39 . MTOR (changed ratio = 0.47) in AMPK signaling pathway belonged to a family of phosphatidylinositol kinase‐related kinases and acted as the target for the cell‐cycle arrest and immunosuppressive effects of the FKBP12‐rapamycin complex.…”

“…38 CCND1 (changed ratio = 0.40) in the cell-cycle pathway acted as a regulatory subunit of CDK4 or CDK6, whose activity was required for cell cycle G1/S transition. Ivermectin could inhibit the growth of mammary tumor cells in a dose-and time-dependent manner by controlling cell-cycle arrest atG1 phase via down-regulation of CDK4 and cyclin D1 expressions 39.…”

Benzyl Isothiocyanate Induces Apoptosis and Inhibits Tumor Growth in Canine Mammary Carcinoma via Downregulation of the Cyclin B1/Cdk1 Pathway

“…Some drugs or chemicals exert anticancer effects by altering cell cycle progression. In canine mammary carcinoma, ivermectin induces cell cycle arrest at the G1 phase ( 19 ). BITC can also induce cell cycle arrest but mostly at the G2 phase ( 8 ).…”