Diacerein's antiproliferative effects alone and with 5-fluorouracil in an Ehrlich solid tumour model: Molecular docking, molecular dynamics Simulation studies, and experimental Verification

Abstract

The current study used an experimental model of mammary gland carcinoma to assess the chemo-sensitizing effectiveness of the combined administration of diacerein and 5-Fluorouracil (5-FU). With docking scores of −8.1, −7.6, and −9.2 kcal/mol, respectively, the molecular docking experiments showed that diacerein exhibits significant binding affinities to Caspase-3, NF-κB, and AKT1. Molecular dynamics Simulations revealed that diacerein has favourable binding free energy (ΔGbind) of −26.7 kcal/mol for Caspase-3, -24.2 kcal/mol for NF-κB, and −39.9 kcal/mol for AKT1, combined with low root mean square deviation (RMSD) values of 3.1 Å, 1.6 Å, and 2.1 Å for the three targets respectively. To validate these findings in vivo, Ehrlich solid tumor (EST) was induced in female Swiss mice. Four groups of animals were randomly assigned: EST + vehicle, EST + 5-FU, EST + diacerein, and EST + combination. Diacerein and 5-FU combination treatment increased EST mice's life span and reduced the solid tumor's weight and volume. Furthermore, diacerein and 5-FU combination significantly suppressed oxidative stress, inhibited AKT phosphorylation, decreased downstream inflammation (NF-κB, TNF-α, IL-1β), and increased apoptosis by modulating Bax, Bcl2, P53, and caspase-3 levels in tumor tissues. In conclusion, by inhibiting the AKT/NF-κB axis, diacerein and 5-FU combination showed possible antiproliferative effectiveness in the EST model.