The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer

Abstract

Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases.In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

“…Recently, this antiparasitic drug has been proposed as a promising anticancer agent in several types of cancer due to its remarkable ability to inhibit tumor growth (16,17). However, the mechanisms underlying the growth-inhibitory effects of ivermectin are still elusive.…”

“…Subsequently, ivermectin, an avermectin derivative, was chemically modified and found to be a more effective compound against a variety of parasites (13). Recently, ivermectin has been identified as a promising anticancer agent for colon cancer, ovarian cancer, melanoma, and leukemia (14)(15)(16)(17). However, the detailed molecular mechanisms underlying ivermectin-mediated suppression of tumor growth remain to be further elucidated.…”

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

“…In parasites, these agents kill by activating glutamate-gated chloride channels and inducing membrane hyperpolarization. In mammalian cells, high concentrations of ivermectin not only activate chloride channels but also induce reactive oxygen species accumulation, block the β-catenin pathway, and inhibit the tumor-suppressive activity of PAK kinase (49)(50)(51)(52). In addition, in virus-infected cells, ivermectin impairs the nuclear import of signaling molecules mediated by α/β importins (53).…”

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

“…Because ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers. 117 Researchers have recently reported a direct interaction between ivermectin and nematode and human tubulin, even at micromolar concentrations. When added to human HeLa cells, ivermectin stabilizes tubulin against depolymerizing effects and prevents replication of the cells in vitro, although the inhibition is reversible.…”