Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

Abstract

Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. Methods GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Results Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. Conclusion The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss

“…We then zeroed in on niclosamide, a previously FDA-approved drug that has been widely used in humans for tapeworm treatment for decades. In addition to its excellent pharmacokinetic/dynamic (PK/PD) properties and safety profile (27, 37–39), niclosamide exhibits outstanding protective effects against cisplatin- and noise-induced hearing loss in both zebrafish and mice when administered systemically. In summary, our work highlights that 1) by using the CMap it is possible to identify compounds that can regulate biological pathways associated with various pathogenic conditions including acquired hearing loss; 2) FDA-approved drugs can be repurposed to prevent cisplatin- and noise-induced hearing loss in clinics; and 3) by targeting multiple biological pathways (37–39) rather than individual pathways, niclosamide can exert better protection than targeting individual pathways against acquired hearing loss.…”

“…Niclosamide has been used safely for nearly 40 years since 1982 for the treatment of parasitic infections in humans (20, 27, 28). Although it has been discontinued in the US due to commercial reasons, it represents an excellent opportunity to repurpose this FDA-approved drug for new indications such as treatment for cancers and hearing loss (37, 48, 49). Niclosamide has many desirable drug properties: (a) it is effective by itself against colon metastatic tumors such as HCT116, SW620, LS174T, SW480, and DLD-1 and is synergistic with cisplatin in a xenograft mouse model of renal cell carcinoma through Wnt/β-catenin signaling (20, 30), it can be delivered orally, which is a significant advantage over other local delivery methods.…”

“…Current ongoing clinical trials for cancer treatment commonly use oral doses up to 2 g/day without any adverse effects (48, 49). This dose was found to lead to serum C max ranging from 0.8 to 18 μM (37). In CD1 mice, IP injection of niclosamide at 10 mg/kg single dose (the otoprotective dose for our NIHL and CIHL) resulted in a C max of 40 μM (38).…”

Combined treatment with niclosamide and camptothecin enhances anticancer effect in U87 MG human glioblastoma cells

“…In addition, niclosamide was demonstrated to reverse enzalutamide resistance in prostate cancer cells [ 28 ]. Oh et al [ 29 ] recently reported that combined treatment with both niclosamide and temozolomide can significantly reduce cell viability, stemness and suppress the invasive capabilities of GBM tumorspheres [ 29 ]. In our previous study, it was also shown that niclosamide can promote cytotoxicity in human glioblastoma cells by downregulating the pro-survival PI3K/AKT, STAT3 and Wnt/β-catenin signal pathways.…”

Breast Cancer Drug Repurposing a Tool for a Challenging Disease

“…Summary of the repurposed drugs for BC discussed in the chapter.Breast Cancer Drug Repurposing a Tool for a Challenging Disease DOI: http://dx.doi.org/10.5772/intechopen.101378 clinical application diseases include type 2 diabetes, endometriosis, neuropathic pain, bacterial and viral infections, including cancer[77]. The anticancer benefits of niclosamide have been shown in many malignancies such as colon cancer, lung cancer, prostate cancer in humans, as well as breast cancer by suppressing various cancer related pathways such as Wnt Notch, mTOR, STAT, and NFκB[78,79]. The combinational treatment of niclosamide with cisplatin overcomes the resistance to cisplatin and induces an inhibitory effect on proliferation in vitro and reduced tumor size in vivo.…”