Anticancer Effects of Niclosamide in Human Glioblastoma

Abstract

Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need.Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n ¼ 21), common glioma lines (n ¼ 5), and noncancer human control cells (n ¼ 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo.Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-kB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy.Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. Clin Cancer Res; 19(15); 4124-36. Ó2013 AACR.

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

“…Some of them were previously suggested as therapeutic candidates for GBM as single agents such as Doxorubicin hydrochloride, 21 Camptothecine (S,C), 22 Proscillaridin A, 15 Pyrivinium pamoate, 23 and Niclosamide. 24 We report Alexidine dihydrochloride, Monensin sodium salt, Lanatoside C, Digitoxigenin, Digoxigenin, Digoxin, Quinacrine dihydrochloride, Terfenadine and Astemizole as novel drugs that can be therapeutic candidates for GBM. Notably, we did not identify Temozolomide (TMZ), the most common drug used as anti-GBM therapy, 2,25 as an effective agent in our screen although it was included, attesting to the unmet need for identifying novel drugs.…”

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

“…In 2011, Sack et al (5) screened 1,280 types of pharmaceutically active compounds using high-throughput screening technology and found niclosamide was able to inhibit colon cancer metastasis. Recently, Wieland et al (6) found that niclosamide is cytotoxic, inhibits cell migration and enhances the effects of chemotherapeutic drugs in glioma cells. Another study (7) found that niclosamide inhibits the growth and induces apoptosis of acute myeloid leukemia cells in vitro and in nude mice, while cells from normal bone marrow were spared.…”

Niclosamide suppresses migration of hepatocellular carcinoma cells and downregulates matrix metalloproteinase-9 expression

“…Niclosamide was originally developed for the treatment of tapeworm infection and is clinically used worldwide (14,15 (18) and inhibition of the canonical Wnt signaling pathway (19). Niclosamide also downregulates the expression of cyclin D1, one of the target molecules of the Wnt pathway, via glycogen synthase kinase-3β (17,20).…”