Stem Cell Pathologies, Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn Medical Center, Bonn, Germany.
Clin Cancer Res. 2013 Aug 1;19(15):4124-36. doi: 10.1158/1078-0432.CCR-12-2895.
Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need.
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 = 21), common glioma lines (n = 5), and noncancer human control cells (n = 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.
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-κB 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.
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.
胶质母细胞瘤是一种高度恶性的、致命的脑肿瘤，目前仍需要有效的药物治疗。
筛选了 160 种合成和天然有毒物质的化合物文库，发现驱虫药尼氯硝唑是一种以前未被识别的临床开发候选药物。考虑到胶质母细胞瘤的细胞和个体间异质性，我们应用了一组短期扩增的原代人脑胶质母细胞瘤细胞（pGBM；n = 21）、常见的神经胶质瘤系（n = 5）和非癌细胞对照（n = 3）作为发现平台和临床前验证。在体外进行了药效学分析、细胞周期进程研究、细胞凋亡、细胞迁移、增殖和多能/自我更新 pGBM 细胞的频率，并用原位异种移植证实了体内的抗癌作用。
尼氯硝唑导致细胞停滞、细胞毒性和抗迁移作用，强烈降低了体外多能/自我更新细胞的频率，并且在暴露后显著降低了 pGBM 在体内的恶性潜能。作用机制分析表明，尼氯硝唑同时抑制了细胞内的 WNT/CTNNB1、NOTCH、mTOR 和 NF-κB 信号通路。此外，组合药物测试确立了神经胶质瘤样本中 NFKBIA 基因座的杂合缺失可以作为预测尼氯硝唑与替莫唑胺协同活性的基因组生物标志物，替莫唑胺是神经胶质瘤治疗的当前标准。
总的来说，我们的数据支持使用 pGBM 来探索化合物文库，以揭示意想不到的先导化合物，例如尼氯硝唑，它可能适合进一步开发用于个性化临床应用。
