Glycyrrhetinic Acid and Autocrine Motility Factor Converge on G6PD Suppression, Oxidative Stress, and Drug Retention to Impair Pancreatic Ductal Adenocarcinoma Cell Growth.

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by chemoresistance and metabolic reprogramming centered on glucose-6-phosphate dehydrogenase (G6PD)-dependent pentose phosphate pathway activity. Exogenously administered autocrine motility factor (AMF) suppresses G6PD at transcriptional and protein levels, elevating intracellular reactive oxygen species (ROS) to cytostatic thresholds. Glycyrrhetinic acid (GA), a bioactive triterpenoid from licorice root, amplifies oxidative stress through mitochondrial membrane disruption, while concurrently downregulating multidrug resistance-associated ABC transporters.

MATERIALS AND

METHODS

Three PDAC cell lines were treated with AMF variants and GA. Cell viability was assessed by MTT assay and clonogenic survival assays. Mechanistic endpoints included DCFDA fluorescence, Western blotting, RT-qPCR, and doxorubicin/Hoechst 33342 fluorescence for drug retention analysis.

RESULTS

Among eight distinct AMF variants, HG-AMF demonstrated the greatest cytotoxic potency both alone and in combination with GA. HG-AMF suppressed G6PD mRNA and protein expression, inducing sustained ROS accumulation confirmed by DCFDA fluorescence. Co-treatment with GA produced enhanced ROS generation, clonogenic suppression, decreased mitochondrial membrane potential, and impaired drug efflux.

CONCLUSION

HG-AMF and GA converge on G6PD-dependent metabolism and chemoresistance pathways, providing a rational basis for their combined application in PDAC therapy.