Suppression of resistance to aminolevulinic acid-based photodynamic therapy in esophageal cell lines by administration of iron chelators in collagen type I matrices

Abstract

Purpose

Photodynamic therapy (PDT) utilizes visible light to activate the cytotoxic effects of photosensitizing drugs. PDT protocols require optimization to overcome treatment resistance and induce a beneficial anti-tumor immune response. The aim of this study was to examine the possibility to suppress the resistance of esophageal cell lines to aminolevulinic acid (ALA)-PDT by administration of iron chelators to induce sufficient cell cytotoxicity under pathophysiologically relevant conditions, mimicking the advanced stages of cancer.

Materials and methods

Effects of ALA-PDT in combination with iron chelators were compared in three esophageal cell lines in conventional monolayers and in 3 D cultures based on collagen type I. Modified colony assay and fluorescence-based live cell imaging, respectively were applied. The latter was used also to test the capability of pre-polarized macrophages to interact with cancer cells subjected to ALA-PDT with or without iron chelators.

Results

Iron chelators were effective in the enhancement of ALA-PDT in all cell lines under both culture conditions. Fluorescence evaluation of cell viability in 3 D cultures indicated the contribution of apoptotic cell death after ALA-PDT, both with and without iron chelators. Engulfment of remnants of dead cancer cells by macrophages in 2 D cultures was indicated, however, the interaction between macrophages and cancer cells in 3 D cultures subjected to ALA-PDT with or without iron chelators was not present.

Conclusions

The potential of iron chelators to enhance ALA-PDT was maintained in 3 D collagen matrices. Although PDT dose (ALA concentration, light exposure time) required modification in a cell line-dependent manner to achieve a comparable effect of PDT alone in conventional monolayers and in collagen matrices, the potential of iron chelators to suppress the resistance of esophageal cells to ALA-PDT was not influenced by a fibrillar collagen matrix.

Keywords:

• Photodynamic therapy
• aminolevulinic acid
• protoporphyrin IX
• chelator
• 3D culture
• macrophage

Acknowledgments

A.M. Kintscher is acknowledged for critically reading and editing the manuscript.

Disclosure statement

The authors report there are no competing interests to declare.

Additional information

Funding

This work was supported by the Scientific Grant Agency of the Slovak Republic under Grant Vega No. 1/0119/19. The research leading to the presented results has received funding also from Laserlab-Europe V (European Union's Horizon 2020 research and innovation program under grant agreement no 871124).

Notes on contributors

Beata Čunderlíková

Beata Čunderlíková, RNDr., PhD, is associate professor at the Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University and researcher at the International Laser Centre-SCSTI in Bratislava, Slovakia, with background in biophysics.

Adriana Kalafutová

Adriana Kalafutová, MSc, is graduate of the Faculty of Natural Sciences, University of SS. Cyril and Methodius in Trnava, Slovakia, with background in biotechnology.

Pavel Babál

Pavel Babál, prof. PhD, MD, is professor of pathology at the Institute of Pathological Anatomy, Faculty of Medicine, Comenius University

Peter Mlkvý

Peter Mlkvý, prof. PhD, MD, is the head of the Department of Laser Medicine at the St. Elisabeth Cancer Institute Hospital and researcher at the International Laser Centre-SCSTI in Bratislava, Slovakia.

Tibor Teplický

Tibor Teplický, PhD, is young carrier investigator at the Institute of Medical Physics, Biophysics, Informatics and Telemedicine, Faculty of Medicine, Comenius University with background in biomedical physics.