title: Growth inhibition of ovarian tumor-initiating cells by niclosamide.
abstract: A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Cheng-Gong Rd., Neihu district, Taipei city 114, Taiwan, ROC.
authors.forename: Yi-Te
authors.initials: YT
authors.lastname: Yo
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Lin
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Wang
authors.forename: Curt
authors.initials: C
authors.lastname: Balch
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Chi-Kuan
authors.initials: CK
authors.lastname: Chen
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chang
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Tim
authors.initials: T
authors.lastname: Huang
authors.forename: Mu-Hsien
authors.initials: MH
authors.lastname: Yu
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Lai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D009534:Niclosamide / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D009534:Niclosamide