ABCG2-mediated suppression of chlorin e6 accumulation and photodynamic therapy efficiency in glioblastoma cell lines can be reversed by KO143.

Autor: Abdel Gaber SA; Laser-Forschungslabor, LIFE-Zentrum, Klinikum der Universität München, Feodor-Lynen-Str. 19, 81377 München, Germany; Pharmaceutical Biology Department, Photochemistry and Photodynamic Therapy Research Group, German University in Cairo, 5th settlement, 11835, New Cairo, Egypt. Electronic address: sara.abdel-gaber@guc.edu.eg., Müller P; Laser-Forschungslabor, LIFE-Zentrum, Klinikum der Universität München, Feodor-Lynen-Str. 19, 81377 München, Germany; Urologische Klinik, Klinikum der Universität München, Marchioninistr. 15, 81377 München, Germany., Zimmermann W; Labor für Tumorimmunologie, LIFE-Zentrum, Klinikum der Universität München, Feodor-Lynen-Str. 19, 81377 München, Germany; Urologische Klinik, Klinikum der Universität München, Marchioninistr. 15, 81377 München, Germany., Hüttenberger D; Apocare Pharma GmbH, Hauptstrasse 198, 33647 Bielefeld,Germany., Wittig R; Institut für Lasertechnologien in der Medizin und Messtechnik an der Universität Ulm, Helmholtzstr. 12, 89081 Ulm, Germany., Abdel Kader MH; Pharmaceutical Biology Department, Photochemistry and Photodynamic Therapy Research Group, German University in Cairo, 5th settlement, 11835, New Cairo, Egypt., Stepp H; Laser-Forschungslabor, LIFE-Zentrum, Klinikum der Universität München, Feodor-Lynen-Str. 19, 81377 München, Germany; Urologische Klinik, Klinikum der Universität München, Marchioninistr. 15, 81377 München, Germany.
Jazyk: angličtina
Zdroj: Journal of photochemistry and photobiology. B, Biology [J Photochem Photobiol B] 2018 Jan; Vol. 178, pp. 182-191. Date of Electronic Publication: 2017 Oct 28.
DOI: 10.1016/j.jphotobiol.2017.10.035
Abstrakt: Background: Photodynamic therapy (PDT) of malignant brain tumors is a promising adjunct to standard treatment, especially if tumor stem cells thought to be responsible for tumor progression and therapy resistance were also susceptible to this kind of treatment. However, some photosensitizers have been reported to be substrates of ABCG2, one of the membrane transporters mediating resistance to chemotherapy. Here we investigate, whether inhibition of ABCG2 can restore sensitivity to photosensitizer chlorin e6-mediated PDT.
Methods: Accumulation of chlorin e6 in wild type U87 and doxycycline-inducible U251 glioblastoma cells with or without induction of ABCG2 expression or ABCG2 inhibition by KO143 was analyzed using flow cytometry. In U251 cells, ABCG2 was inducible by doxycycline after stable transfection with a tet-on expression plasmid. Tumor sphere cultivation under low attachment conditions was used to enrich for cells with stem cell-like properties. PDT was done on monolayer cell cultures by irradiation with laser light at 665nm.
Results: Elevated levels of ABCG2 in U87 cells grown as tumor spheres or in U251 cells after ABCG2 induction led to a 6-fold lower accumulation of chlorin e6 and the light dose needed to reduce cell viability by 50% (LD50) was 2.5 to 4-fold higher. Both accumulation and PDT response can be restored by KO143, an efficient non-toxic inhibitor of ABCG2.
Conclusion: Glioblastoma stem cells might escape phototoxic destruction by ABCG2-mediated reduction of photosensitizer accumulation. Inhibition of ABCG2 during photosensitizer accumulation and irradiation promises to restore full susceptibility of this crucial tumor cell population to photodynamic treatment.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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