Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In
Aaron J Sorrin1, Cindy Liu1, Julia Cicalo1
1Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
Abstract:
The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are "photodynamically primed", or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
Insights
This study combines photodynamic priming (PDP) with EP4 inhibition to reduce ovarian cancer cell migration. This novel approach targets key signaling pathways for improved anti-metastatic effects.
Area of Science:
- Oncology
- Photochemistry
- Molecular Biology
Background:
- Photodynamic agents combined with biological inhibitors show promise for advanced cancer treatment.
- Photodynamic treatment (PDT) generates reactive oxygen species, inducing cancer cell death and priming survivors for enhanced drug response.
- Prostaglandin E2 receptor 4 (EP4) antagonists are being explored for cancer therapy.
Purpose of the Study:
- To investigate a novel combination regimen of photodynamic priming (PDP) and EP4 inhibition.
- To evaluate the efficacy of this combination in reducing ovarian cancer cell migration and invasion.
- To elucidate the underlying molecular signaling pathways modulated by this combined treatment.
Main Methods:
- Utilized two human ovarian cancer cell lines (OVCAR-5 and CAOV3) for in vitro studies.
- Administered photodynamic priming (PDP) using red light activation of benzoporphyrin derivative (BPD) or an EGFR-targeted BPD-cetuximab conjugate.
- Combined PDP with EP4 inhibition and analyzed signaling cascades via immunoblotting.
Main Results:
- The combination of PDP and EP4 inhibition significantly reduced migration and invasion of ovarian cancer cells in vitro.
- EGFR-targeted PDP combined with EP4 inhibition led to co-inhibition of EGFR, CREB, and ERK1/2 signaling pathways.
- Identified specific signaling cascades modulated by the combination therapy.
Conclusions:
- The combination of photodynamic priming and EP4 inhibition presents a promising strategy to enhance anti-metastatic effects in ovarian cancer.
- Targeting EGFR, CREB, and ERK1/2 pathways is crucial for the efficacy of this molecular-targeted photochemical approach.
- This study provides insights for developing novel therapeutic strategies against metastatic ovarian cancer.
