Predictive biomarkers for 5‐ALA‐PDT can lead to personalized treatments and overcome tumor‐specific resistances release_c4fqeynilfgmdjzrk2e34rieqi

by Maria Mastrangelopoulou, Mantas Grigalavicius, Tine H. Raabe, Ellen Skarpen, Petras Juzenas, Qian Peng, Kristian Berg, Theodossis Theodossiou

Published in Cancer Reports by Wiley.

2020   Volume 5, Issue 12, e1278

Abstract

Photodynamic therapy (PDT) is a minimally invasive, clinically approved therapy with numerous advantages over other mainstream cancer therapies. 5-aminolevulinic acid (5-ALA)-PDT is of particular interest, as it uses the photosensitiser PpIX, naturally produced in the heme pathway, following 5-ALA administration. Even though 5-ALA-PDT shows high specificity to cancers, differences in treatment outcomes call for predictive biomarkers to better stratify patients and to also diversify 5-ALA-PDT based on each cancer's phenotypic and genotypic individualities. The present study seeks to highlight key biomarkers that may predict treatment outcome and simultaneously be exploited to overcome cancer-specific resistances to 5-ALA-PDT. We submitted two glioblastoma (T98G and U87) and three breast cancer (MCF7, MDA-MB-231, and T47D) cell lines to 5-ALA-PDT. Glioblastoma cells were the most resilient to 5-ALA-PDT, while intracellular production of 5-ALA-derived protoporphyrin IX (PpIX) could not account for the recorded PDT responses. We identified the levels of expression of ABCG2 transporters, ferrochelatase (FECH), and heme oxygenase (HO-1) as predictive biomarkers for 5-ALA-PDT. GPX4 and GSTP1 expression vs intracellular glutathione (GSH) levels also showed potential as PDT biomarkers. For T98G cells, inhibition of ABCG2, FECH, HO-1, and/or intracellular GSH depletion led to profound PDT enhancement. Inhibition of ABCG2 in U87 cells was the only synergistic adjuvant to 5-ALA-PDT, rendering the otherwise resistant cell line fully responsive to 5-ALA-PDT. ABCG2 or FECH inhibition significantly enhanced 5-ALA-PDT-induced MCF7 cytotoxicity, while for MDA-MB-231, ABCG2 inhibition and intracellular GSH depletion conferred profound synergies. FECH inhibition was the only synergism to ALA-PDT for the most susceptible among the cell lines, T47D cells. This study demonstrates the heterogeneity in the cellular response to 5-ALA-PDT and identifies biomarkers that may be used to predict treatment outcome. The study also provides preliminary findings on the potential of inhibiting specific molecular targets to overcome inherent resistances to 5-ALA-PDT.
In text/plain format

Archived Content

There are no accessible files associated with this release. You could check other releases for this work for an accessible version.

"Dark" Preservation Only
Save Paper Now!

Know of a fulltext copy of on the public web? Submit a URL and we will archive it

Type  article-journal
Stage   published
Date   2020-07-31
Language   en ?
DOI  10.1002/cnr2.1278
PubMed  32737955
PMC  PMC9780429
Container Metadata
Open Access Publication
In DOAJ
In Keepers Registry
ISSN-L:  2573-8348
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: 450c1011-7ba2-4ad4-b507-2d7eb226cec7
API URL: JSON