Redox-mediated activation of PI3K/PTEN pathways by A. baumannii OMV–V. myrtillus conjugate in pancreatic cancer cells

Abstract

Pancreatic cancer (PC) is one of the most aggressive malignancies of the digestive system, characterized by late diagnosis, resistance to conventional therapies, and poor survival outcomes. Therefore, the development of novel, effective, and targeted therapeutic strategies is urgently needed. This study aimed to evaluate the anticancer potential of Acinetobacter baumannii-derived outer membrane vesicles (OMVs) conjugated with Vaccinium myrtillus extract, a low-toxicity natural compound, against pancreatic cancer cells. For this purpose, V. myrtillus was conjugated with A. baumannii-derived OMVs, and the antimicrobial activity of the conjugate was assessed using disk diffusion, minimum inhibitory concentration, time-kill kinetics, and biofilm inhibition assays. The anticancer effects were investigated by treating PANC-1 pancreatic cancer cells and healthy fibroblast cells with OMVs (50 µg/mL) and increasing concentrations of V. myrtillus (5–250 µg/mL). After 24 h, cell viability and cytotoxicity (MTT, LDH), oxidative stress parameters (TAS, TOS, SOD, GR), PI3K/AKT/PTEN signaling pathway components, apoptotic markers (Annexin V/PI, BAX, Bcl-2, Caspase-8), and inflammatory cytokines (IL-1β, IL-10) were analyzed. The OMV–V. myrtillus conjugate (50 µg/mL OMV +250 µg/mL V. myrtillus) significantly reduced cell viability by approximately 60% through disruption of intracellular redox balance. Elevated oxidative stress triggered apoptotic signaling, approximately increased 50% LDH release, and enhanced inflammatory responses. Especially 50 µg/mL OMV +250 µg/mL V. myrtillus treatment group compared to the control group, which approximately increased to 1-fold IL-1β rate. Furthermore, the 50 µg/mL OMV +250 µg/mL V. myrtillus treatment group showed approximately a 0.75-fold increase in PTEN and BAX gene expression, accompanied by a correlated decrease in AKT and BCL-2 gene expression, compared to the control group. These results suggest that OMV-mediated delivery of V. myrtillus represents a promising synergistic therapeutic approach for treatment-resistant pancreatic cancer.

Graphical abstract

The alternative text for this image may have been generated using AI.