PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Int J Mol Sci. 2021 Feb 28;22(5):2464. doi: 10.3390/ijms22052464.
Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified (), , signal transducer and activator of transcription 3 (), and cluster of differentiation 44 () as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of , and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; , , and , and the stem cell marker, , to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI) values ranged 0.23~5.13 μM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (//) signaling and upregulate the tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic.
尽管采用了标准的手术、放疗和化疗等方法进行治疗，但胶质母细胞瘤（GBM）仍然难以治疗，这是由于胶质瘤干细胞（GSCs）和治疗耐药性导致肿瘤复发。在这项研究中，我们使用基于计算机的随机预测和靶标鉴定来评估我们新合成的尼氯柳胺衍生化合物 NSC765689 对 GBM 致癌信号的靶向作用。通过靶标预测分析，我们鉴定出 ()、()、信号转导子和转录激活子 3 () 和分化簇 44 () 为 NSC765689 的潜在可用药靶标。与相邻正常样本相比，上述信号通路也被预测在 GBM 肿瘤样本中过度表达。此外，我们还使用生物信息学工具鉴定出 microRNA (miR)-135b 是 GBM 样本中下调最明显的 microRNA 之一，据报道，miR-135b 通过抑制 () 的表达而上调，从而抑制 GBM 肿瘤发生特性和干细胞特性。我们进一步对 NSC765689 与 GBM 癌基因（//）、（//）和（//）以及干细胞标志物（//）进行了计算机分子对接，以预测蛋白质-配体相互作用。结果表明，与我们实验室最近发表的前身 LCC09 相比，NSC765689 表现出更强的结合亲和力，并被证明能抑制 GBM 干细胞特性和耐药性。此外，我们使用美国国立癌症研究所（NCI）的 60 个人类肿瘤细胞系进行了体外抗癌作用筛选，包括 NSC765689 对 GBM 细胞的抗增殖和细胞毒性活性，以及 50%细胞生长抑制（GI）值范围为 0.23~5.13 μM。综上所述，使用计算机预测和靶标鉴定揭示，NSC765689 可能是一种潜在的药理先导化合物，可调节 GBM 癌基因（//）信号并上调肿瘤抑制因子。因此，我们将进一步进行体外和体内研究，以验证 NSC765689 作为一种新型潜在 GBM 治疗药物的疗效。
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