PDF(Pubmed)
Abstract：
FOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 µM in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 µM and in BT-20 cells and at 70 µM in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.
摘要：
FOXM1，一种原癌基因转录因子，在癌症发展和癌症治疗抵抗中起着关键作用，特别是在乳腺癌中。因此，这项研究旨在通过对药物数据库的计算筛选来确定潜在的FOXM1抑制剂，然后在体外验证它们对乳腺癌细胞的抑制活性。在计算机模拟研究中，使用FOXM1抑制剂进行药效团建模，FDI-6，然后对DrugBank和Selleckchem数据库进行虚拟筛选。选择的药物进行分子对接，并对FOXM1的晶体结构进行了预处理，用于对接模拟。体外研究包括MTT测定以评估细胞毒性，和蛋白质印迹分析以评估蛋白质表达水平。我们的研究通过计算机筛选和分子对接确定了泮托拉唑和雷贝拉唑是潜在的FOXM1抑制剂。分子动力学模拟证实了这些药物与FOXM1的稳定相互作用。体外实验表明，泮托拉唑和雷贝拉唑在有效浓度下都表现出强的FOXM1抑制作用，并表现出对细胞增殖的抑制作用。雷贝拉唑在BT-20和MCF-7细胞系中显示10µM的抑制剂活性。泮托拉唑在30μM和BT-20细胞中表现出FOXM1抑制作用，在MCF-7细胞中表现出70μM抑制作用，分别。我们目前的研究提供了第一个证据，证明雷贝拉唑和泮托拉唑可以结合FOXM1并抑制其活性和下游信号，包括eEF2K和pEF2，在乳腺癌细胞中。这些发现表明雷贝拉唑和泮托拉唑抑制FOXM1和乳腺癌细胞增殖，它们可用于FOXM1靶向治疗乳腺癌或由FOXM1驱动的其他癌症。
