Modulation of erlotinib activity by supramolecular and nanoscale interactions in pancreatic cancer cells
Abstract:
Pancreatic cancer remains one of the most aggressive malignancies with limited therapeutic options and poor prognosis. Erlotinib (OSI-774), a small-molecule tyrosine kinase inhibitor (TKI), is clinically used in combination with gemcitabine, yet its efficacy is limited by modest improvements in overall survival (OS) and significant side effects. The aggregation of erlotinib in aqueous solutions further restricts its bioavailability. This study investigates the potential of Congo red (CR), a supramolecular carrier, to enhance the therapeutic impact of erlotinib against pancreatic cancer cells. Biophysical analyses using UV-visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) confirmed the formation of stable CR-erlotinib co-aggregates with optimal molar ratio of 5:1. The effects of erlotinib alone and in combination with CR (CR:OSI-774) were evaluated on two pancreatic cancer cell lines (PANC-1 and BxPC-3). CR:OSI-774 complexes demonstrated significantly lower IC50 and IC90 values compared to erlotinib monotherapy, indicating enhanced anti-proliferative effects. While erlotinib induced apoptosis, CR:OSI-774 primarily triggered necrotic cell death. Importantly, both compounds significantly inhibited cancer cell migration and invasion, with CR:OSI-774 showing superior inhibition of invasive capacity. CR alone did not negatively affect cell viability or apoptosis/necrosis rates. Nanomechanical measurements using atomic force microscopy revealed an increase in cellular stiffness after treatment, particularly in cells exposed to the CR-erlotinib complex, suggesting changes in cytoskeletal organization associated with reduced motility. Furthermore, quantitative protein analysis using the Jess capillary electrophoresis system revealed a decrease in AKT phosphorylation without significant changes in total AKT levels, indicating effective modulation of EGFR signaling via supramolecular aggregation. These findings suggest that supramolecular aggregation with CR represents a promising strategy to enhance erlotinib efficacy in pancreatic cancer therapy while potentially reducing systemic toxicity. The approach opens new avenues for personalized medicine and targeted anti-cancer therapy.
Insights
Congo red enhances erlotinib's anti-pancreatic cancer effects by forming co-aggregates. This supramolecular approach improves drug efficacy and reduces cell invasion, offering a promising strategy for pancreatic cancer therapy.
Area of Science:
- Biochemistry
- Materials Science
- Oncology
Background:
- Pancreatic cancer is an aggressive malignancy with limited treatment options and poor patient outcomes.
- Erlotinib (OSI-774), a tyrosine kinase inhibitor, shows limited efficacy and bioavailability issues in pancreatic cancer treatment.
- Drug aggregation in aqueous solutions restricts erlotinib's therapeutic potential.
Purpose of the Study:
- To investigate Congo red (CR) as a supramolecular carrier to enhance erlotinib's efficacy against pancreatic cancer.
- To evaluate the anti-cancer effects of CR-erlotinib complexes on pancreatic cancer cell lines.
- To explore the mechanism of action of CR-erlotinib complexes on cancer cell proliferation, death, migration, and signaling pathways.
Main Methods:
- Formation and characterization of CR-erlotinib co-aggregates using UV-visible spectroscopy and dynamic light scattering.
- Assessment of anti-proliferative effects (IC50, IC90) and cell death (apoptosis, necrosis) on PANC-1 and BxPC-3 cell lines.
- Evaluation of cell migration and invasion inhibition using nanomechanical measurements (atomic force microscopy) and protein analysis (Jess capillary electrophoresis).
Main Results:
- Stable CR-erlotinib co-aggregates were formed at a 5:1 molar ratio, enhancing anti-proliferative effects compared to erlotinib alone.
- CR-erlotinib complexes induced necrotic cell death, while erlotinib induced apoptosis, and significantly inhibited cancer cell migration and invasion.
- Treatment increased cellular stiffness and modulated EGFR signaling by decreasing AKT phosphorylation.
Conclusions:
- Supramolecular aggregation with Congo red enhances erlotinib efficacy against pancreatic cancer cells.
- The CR-erlotinib complex shows superior inhibition of cancer cell invasion and motility.
- This strategy holds promise for improving pancreatic cancer therapy and potentially reducing systemic toxicity.
