Identification of potential inhibitors for drug resistance in acute lymphoblastic leukemia through differentially expressed gene analysis and in silico screening

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Başak Özay , Ezgi Yağmur Tükel , Gizem Ayna Duran , Yağmur Kiraz
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Abstract

Acute lymphoblastic leukemia (ALL) is a disease of lymphocyte origin predominantly diagnosed in children. While its 5-year survival rate is high, resistance to chemotherapy drugs is still an obstacle. Our aim is to determine differentially expressed genes (DEGs) related to Asparaginase, Daunorubicin, Prednisolone, and Vincristine resistance and identify potential inhibitors via docking. Three datasets were accessed from the Gene Expression Omnibus database; GSE635, GSE19143, and GSE22529. The microarray data was analyzed using R4.2.0 and Bioconductor packages, and pathway and protein-protein interaction analysis were performed. We identified 1294 upregulated DEGs, with 12 genes consistently upregulated in all four resistant groups. KEGG analysis revealed an association with the PI3K-Akt pathway. Among DEGs, 33 hub genes including MDM2 and USP7 were pinpointed. Within common genes, CLDN9 and HS3ST3A1 were subjected to molecular docking against 3556 molecules. Following ADMET analysis, three drugs emerged as potential inhibitors: Flunarizine, Talniflumate, and Eltrombopag. Molecular dynamics analysis for HS3ST3A1 indicated all candidates had the potential to overcome drug resistance, Eltrombopag displaying particularly promising results. This study promotes a further understanding of drug resistance in ALL, introducing novel genes for consideration in diagnostic screening. It also presents potential inhibitor candidates to tackle drug resistance through repurposing.

Abstract Image

通过差异表达基因分析和硅学筛选鉴定急性淋巴细胞白血病耐药性的潜在抑制剂
急性淋巴细胞白血病(ALL)是一种主要发生于儿童的淋巴细胞源性疾病。虽然其 5 年生存率很高,但对化疗药物的耐药性仍是一个障碍。我们的目的是确定与天冬酰胺酶、达诺比星、泼尼松龙和长春新碱耐药性相关的差异表达基因(DEGs),并通过对接确定潜在的抑制剂。从基因表达总库数据库中获取了三个数据集:GSE635、GSE19143 和 GSE22529。我们使用 R4.2.0 和 Bioconductor 软件包分析了微阵列数据,并进行了通路和蛋白质相互作用分析。我们发现了 1294 个上调的 DEGs,其中 12 个基因在所有四个抗性组中都持续上调。KEGG分析显示,这些基因与PI3K-Akt通路有关。在 DEGs 中,确定了包括 MDM2 和 USP7 在内的 33 个枢纽基因。在常见基因中,CLDN9和HS3ST3A1与3556个分子进行了分子对接。经过 ADMET 分析,三种药物成为潜在的抑制剂:Flunarizine、Talniflumate 和 Eltrombopag。HS3ST3A1 的分子动力学分析表明,所有候选药物都具有克服耐药性的潜力,其中 Eltrombopag 的结果尤其令人鼓舞。这项研究促进了对 ALL 耐药性的进一步了解,引入了新的基因供诊断筛选时考虑。它还提出了潜在的候选抑制剂,以通过再利用来解决耐药性问题。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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