Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres
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ORIGINAL ARTICLE – CANCER RESEARCH
Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres Hyeong‑Cheol Oh1 · Jin‑Kyoung Shim1 · Junseong Park1 · Ji‑Hyun Lee1 · Ran Joo Choi1 · Nam Hee Kim2 · Hyun Sil Kim2 · Ju Hyung Moon1 · Eui Hyun Kim1 · Jong Hee Chang1 · Jong In Yook2 · Seok‑Gu Kang1,3 Received: 12 April 2020 / Accepted: 18 July 2020 © The Author(s) 2020
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. Keywords Glioblastoma · Invasion · Niclosamide · Temozolomide · Tumorsphere
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03330-7) contains supplementary material, which is available to authorized users. * Jong In Yook [email protected] * Seok‑Gu Kang [email protected] 1
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50‑1 Yonsei‑ro, Seodaemun‑gu, Seoul 03722, Republic of Korea
2
Department of Oral Pathology, Yonsei University College of Dentistry, 50‑1 Yonsei‑ro, Seodaemun‑gu, Seoul 03722, Republic of Korea
3
Department of Medical Science, Yonsei University Graduate School, 50‑1 Yonsei‑ro, Seodaemun‑gu, Seoul 03722, Republic of Korea
Introduction Patients with glioblastoma (GBM), the most common type of primary brain tumor, have a poor prognosis, with a median overall survival of about 17.5 months in Korea (Kim et al.
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