Dey Smita, Mathur Prerika, Mukherjee Sudeshna, Chowdhury Rajdeep, Majumder Syamantak, Roy Aniruddha, Chowdhury Shibasish
Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Pilani Campus, Vidya Vihar, Pilani, Rajasthan, 333031, India.
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Vidya Vihar, Pilani, Rajasthan, 333031, India.
Sci Rep. 2025 Jul 1;15(1):20560. doi: 10.1038/s41598-025-05054-5.
GBM is one of the most aggressive malignancies, having the greatest fatality rate and average life years lost. The current standard medicine, temozolomide (TMZ), is ineffective, requiring the development of new treatments. However, identifying and introducing a novel medicine takes time and money. In this context, repurposing FDA-approved drugs can be a novel yet efficient alternative method. Here, we, therefore, investigated the differential expression signatures of genes of patients suffering from GBM from publicly available GEO datasets and constructed a connectivity map. Functional annotation and KEGG pathway analysis showed dysregulated molecular activities and pathways. Based on their gene ontologies, putative key genes and hub genes linked with the disease were identified, and the C-MAP database was scanned for FDA-approved medicinal compounds that could alter hub gene expression or associated pathways. Our in-silico investigation showed that Gemfibrozil (Gem) and Doxylamine (Doxy) might reverse GBM disease patterns by deregulating GBM-related genes. Evaluation of the GBM inhibitory potential of these drugs through in-vitro and three-dimensional spheroid assay showed promising results. These drugs were more cytotoxic than TMZ; however, they synergised with TMZ as well. Interestingly, the cellular homeostatic process autophagy which has been implicated significantly in GBM pathogenesis and therapy resistance, was found to be inhibited by the drugs Gemfibrozil and Doxylamine, signifying their prospective potential. Therefore, in this study, we, for the first time, identify drugs with the ability to cross the blood brain barrier (BBB), with potential cytotoxic effects beyond TMZ, and with autophagy inhibitory potential, which can be further explored for repurposing against GBM.
胶质母细胞瘤（GBM）是最具侵袭性的恶性肿瘤之一，致死率最高，平均寿命损失年数最多。目前的标准药物替莫唑胺（TMZ）效果不佳，需要开发新的治疗方法。然而，识别和引入一种新药需要时间和金钱。在此背景下，重新利用美国食品药品监督管理局（FDA）批准的药物可能是一种新颖而有效的替代方法。因此，在这里，我们从公开可用的基因表达综合数据库（GEO）数据集中研究了GBM患者基因的差异表达特征，并构建了一个连接图谱。功能注释和京都基因与基因组百科全书（KEGG）通路分析显示分子活性和通路失调。基于它们的基因本体，确定了与该疾病相关的假定关键基因和枢纽基因，并在C-MAP数据库中搜索可以改变枢纽基因表达或相关通路的FDA批准的药用化合物。我们的计算机模拟研究表明，吉非罗齐（Gem）和多西拉敏（Doxy）可能通过调节与GBM相关的基因来逆转GBM疾病模式。通过体外和三维球体试验评估这些药物对GBM的抑制潜力显示出有希望的结果。这些药物比TMZ更具细胞毒性；然而，它们也与TMZ协同作用。有趣的是，细胞稳态过程自噬在GBM发病机制和治疗耐药性中具有重要意义，发现吉非罗齐和多西拉敏这两种药物可抑制自噬，这表明了它们的潜在潜力。因此，在本研究中，我们首次鉴定出具有穿越血脑屏障（BBB）能力、具有超越TMZ的潜在细胞毒性作用以及具有自噬抑制潜力的药物，这些药物可进一步探索用于重新治疗GBM。
