title: Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.
abstract: Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27705, USA.
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.forename: Xiao Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Vandeusen
authors.forename: David
authors.initials: D
authors.lastname: Hsu
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Clary
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000072261:Dishevelled Proteins; D005347:Fibroblasts / Q000187:drug effects; D017491:Genes, APC; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009534:Niclosamide / Q000493:pharmacokinetics / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010750:Phosphoproteins / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000871:Anthelmintics; D000970:Antineoplastic Agents; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; D016328:NF-kappa B; D009944:Organoplatinum Compounds; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D000077150:Oxaliplatin; D009534:Niclosamide; D058570:TOR Serine-Threonine Kinases