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

## TL;DR

This study evaluates natural compounds for their ability to kill pancreatic cancer cells, finding that certain naphthoquinones are highly effective.

## Contribution

The study identifies specific natural compounds with potent antiproliferative and cytotoxic effects on pancreatic cancer cells.

## Key findings

- β-lapachone showed the highest antiproliferative and cytotoxic activity against PDAC cell lines with LC50 values of 4.00 μM and 3.89 μM.
- Polymatin A exhibited moderate activity with LC50 values of 16.11 μM and 20.00 μM for PANC-1 and MIAPaCa-2 cells.
- Naphthoquinones induced mitochondrial superoxide modulation and membrane depolarization, indicating a redox-active mechanism.

## Abstract

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 naphthoquinones (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. The naphtoquinones 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.