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.

Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest

“…In recent years, it has been suggested that niclosamide inhibited cancer growth and metastasis in epithelium-derived tumors, including prostate (8), lung (9,10), head and neck (11), and ovarian cancer (12,13). However, its effects on mesenchymal tumors (e.g., osteosarcoma) are unclear.…”

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

“…injections) or vehicle (DMSO 5%) alone (10 mice/group) (15). Stock solution of niclosamide (2 mg/ml in DMSO) was prepared and kept at 220˚C.…”

“…Recently, several groups have independently reported that niclosamide is active against certain solid cancers (13)(14)(15). This drug acts through different signaling pathways such as STAT3 and Wnt/b-catenin pathways: niclosamide inhibits nuclear translocation and transcriptional activity of STAT3, and also inhibits b-catenin stabilization and b-catenin/TCF transcription-activating complex (16).…”

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.…”

“…Signaling pathways Cancer cells [45], osteosarcoma [37], STAT3 CSCs [46], Wnt/β-catenin ovarian cancer [43], prostate cancer [36], NSCLC/ c-Jun-ROS [35], colorectal cancer/TNIK [30].…”