5-Fluorouracil and Rumex obtusifolius extract combination trigger A549 cancer cell apoptosis: Uncovering PI3K/Akt inhibition by in vitro and in silico approaches

In this study, the objective was to explore novel strategies for improving the efficacy of anticancer therapy. The focus was on investigating the antiproliferative effects of combining Rumex obtusifolius extract (RO) with the chemotherapeutic agent 5-Fluorouracil (5-FU) in non-small A549 lung cancer cells (NSCLC). Key factors such as the PI3K/Akt cell signaling system, cytokines, growth factors (TNFa, VEGFa), and enzymes (Arginase, NOS, COX-2, MMP-2) were analyzed to assess the impact of the combination treatment. Results revealed that the combined treatment of 5-FU and RO demonstrated a significant reduction in TNFa levels, comparable to the effect observed with RO alone. RO was found to modulate the PI3K/Akt pathway, influencing the phosphorylated and total amounts of these proteins during the combined treatment. Notably, COX-2, a key player in inflammatory processes, substantially decreased with the combination treatment. Caspase-3 activity, indicative of apoptosis, increased by 1.8 times in the combined treatment compared to separate treatments. In addition, in silico analyses explored the binding affinities and interactions of RO's major phytochemicals with intracellular targets, revealing a high affinity for PI3K and Akt. These findings suggest that the combined treatment induces apoptosis in A549 cells by regulating the PI3K/Akt pathway.