Niclosamide is a potential therapeutic for familial adenomatosis polyposis by disrupting Axin-GSK3 interaction

Abstract

The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified. In this study, we show that niclosamide directly targets Axin-GSK3 interaction, at least in part, resulting in suppression of Wnt/Snail-mediated EMT. In vitro and in vivo, disruption of Axin-GSK3 complex by niclosamide induces mesenchymal to epithelial reversion at nM concentrations, accompanied with suppression of the tumorigenic potential of colon cancer. Niclosamide treatment successfully attenuates Snail abundance while increasing E-cadherin abundance in xenograft tumor. Notably, oral administration of niclosamide significantly suppressed adenoma formation in an APC-MIN mice model, indicating that niclosamide is an effective therapeutic for familial adenomatosis polyposis (FAP) patients. In this study, we identified a novel target to control the canonical Wnt pathway and Snail-mediated EMT program, and discovered a repositioned therapeutics for FAP patients.

Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist‐mediated CD10 expression

“…That study further indicated that CD10 may play a certain role during the EMT by Twist1 . Actually, niclosamide was also reported to inhibit the EMT in breast cancer and colon cancer cells . Our results showed that knockdown or overexpression of Twist in SK‐Hep‐1 and Huh7 cells respectively downregulated and upregulated CD10 expression.…”

Canonical Wnt/β‐catenin and Notch signaling regulate animal/vegetal axial patterning in the cephalochordate amphioxus

“…Next, the role of cWnt signaling on A/V axial patterning was examined using a loss‐of‐function study. Treatment with 10 μM niclosamide (5‐chloro‐ N ‐(2‐chloro‐4‐nitrophenyl)‐2‐hydroxybenzamide), a cWnt signaling inhibitor (Ahn et al, ; Chen et al, ; Mook et al, ), from early gastrulation caused the ectodermal and endomesodermal cell layers to develop in an abnormal shape and strongly expanded vegetal expression of foxq2 (Figures S2A and S2D). In contrast, brachyury expression became narrow compared with that of control embryos (Figures S2B and S2E).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”

“…Furthermore, niclosamide inhibited not only signal transduction, but also targeted mitochondria in cancer cells resulting in cell cycle arrest, growth inhibition and apoptosis [49 -51]. Niclosamide may work as therapeutic for familial adenomatosis polyposis (FAP) by disrupting the axin-GSK3 interaction and for colon cancer in synergizing with erlotinib [52,53]. Accordingly, clinical trials administrating niclosamide for the treatment of resectable/metastatic colon cancer and castration-resistant, metastatic prostate cancer are recruiting.…”

“…Signaling pathways were inhibited in osteosarcoma and, especially, Wnt/β-catenin signal transduction in ovarian cancer cells and via GSK3 and STAT3 in CSCs and colon cancer [41,47,50,52,53]. In prostate cancer cells the STAT3 -androgen receptor (AR) axis was inhibited by niclosamide and cell death in NSCLC was effected via c-JUN stress kinase and generation of ROS [39,40].…”