IntroductionChemotherapy resistance is a critical bottleneck in lung cancer treatment, significantly limiting the clinical efficacy of drugs like paclitaxel. This study investigated the cytotoxic and chemosensitizing potential of hexane, acetone, and hydroalcoholic extracts from Eryngium heterophyllum Engelm. [Apiaceae] to enhance therapeutic response in A549 lung cancer cells.MethodsExtracts were obtained by maceration and their antiproliferative activity was determined using crystal violet assays. Synergistic interactions between extracts and paclitaxel were quantified using the Chou–Talalay combination index. Mechanistic studies included DAPI staining for nuclear fragmentation, immunofluorescence for P-glycoprotein expression, and flow cytometry to assess functional doxorubicin retention. Chemical profiling was performed via Gas Chromatography-Mass Spectrometry.ResultsThe hexane extract exhibited the highest intrinsic cytotoxicity (IC50 = 25.1 ± 1.1 μg/mL). Notably, combining sub-cytotoxic concentrations of the extracts with paclitaxel reduced the drug’s IC50 by 10 to 14-fold, with the acetone extract showing the strongest synergism. These combinations induced significant apoptotic nuclear fragmentation. Furthermore, all extracts increased intracellular doxorubicin retention to levels comparable to the reference inhibitor verapamil, suggesting potent inhibition of P-gp mediated efflux.DiscussionThese findings demonstrate that E. heterophyllum extracts exhibit a dual biological effect by providing direct antiproliferative activity while also enhancing the response of A549 cells to paclitaxel. The observed effects may be associated with modulation of drug transport-related mechanisms, including increased intracellular doxorubicin retention and changes in P-gp associated activity. This species represents a promising source of plant-derived metabolites as complementary agents for improving chemotherapy response in lung cancer cells.