Synergistic drug repurposing strategy identifies doxorubicin and paclitaxel as potential combination therapy for...

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma, characterized by clinical heterogeneity and chemoresistance. About 30% of patients relapse or develop refractory disease despite therapy. This study aimed to identify repurposed antitumor agents with potentially synergistic efficacy against DLBCL through an integrative in silico and in vitro approach.

DLBCL-associated genes were obtained from DisGeNET and GeneCards, and overlapping genes (OGs) were identified via Venny v2.1.0. Functional enrichment analysis of OGs was performed using ShinyGO v0.77, while protein-protein interaction (PPI) networks were generated with STRING v11.5 and visualized in Cytoscape v3.10 to identify hub genes. Expression validation was conducted using GEPIA2. Potential drugs were screened from DSigDB and DrugMAP, and molecular docking using AutoDock Vina v1.2.0 assessed binding affinities of candidate compounds with hub gene proteins. In vitro assays employing 2PK-3 DLBCL cells evaluated cytotoxicity and oxidative stress induced by Doxorubicin and Paclitaxel, both alone and combined, through morphological analysis, MTT viability, and ROS assays.

A total of 144 OGs were identified, with enrichment analysis highlighted PI3K-Akt signalling, apoptosis, and cell cycle regulation. Seven hub genes were identified, among which AKT1, TP53, MYC, and STAT3 emerged as key regulatory targets. Docking demonstrated high binding affinities (≤-8.0 kcal/mol) for Doxorubicin, Paclitaxel, Sorafenib, Masoprocol, and Bortezomib. Combined Doxorubicin and Paclitaxel treatment exhibited enhanced cytotoxicity, morphological disruption, and elevated ROS generation compared to single-drug treatments.

This integrative study highlights the therapeutic potential of Doxorubicin and Paclitaxel against DLBCL, supporting drug repurposing as a promising strategy for developing effective combinatorial therapies.