In Vitro Evaluation of Natural Sesquiterpene Lactones and Naphthoquinones Against Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds—sesquiterpene lactones (achillin and polymatin A) and naphthoquinone (α, β-lapachone and lapachol)—in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC50 values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC50 of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure–activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research.