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ABCG2 influence on the efficiency of photodynamic therapy in glioblastoma cells
Patricia Müller1, Sara A Abdel Gaber2, Wolfgang Zimmermann3
1Laser Forschungslabor, LIFE Center, University Hospital, LMU Munich, Fraunhoferstr. 20, 82152 Planegg, Germany; Labor für Tumorimmunologie, LIFE Center, University Hospital, LMU Munich, Fraunhoferstr. 20, 82152, Planegg, Germany.
Background:
Photodynamic therapy with 5-aminolevulinic acid (5-ALA PDT) is a promising novel therapeutic approach in the therapy of malignant brain tumors. 5-ALA occurs as a natural precursor of protoporphyrin IX (PpIX), a tumor-selective photosensitizer. The ATP-binding cassette transporter ABCG2 plays a physiologically significant role in porphyrin efflux from living cells. ABCG2 is also associated with stemness properties. Here we investigate the role of ABCG2 on the susceptibility of glioblastoma cells to 5-ALA PDT.
Methods:
Accumulation of PpIX in doxycycline-inducible U251MG glioblastoma cells with or without induction of ABCG2 expression or ABCG2 inhibition by KO143 was analyzed using flow cytometry. In U251MG cells, ABCG2 was inducible by doxycycline after stable transfection with a tet-on expression plasmid. U251MG cells with high expression of ABCG2 were enriched and used for further experiments (sU251MG-V). PDT was performed on monolayer cell cultures by irradiation with laser light at 635 nm.
Results:
Elevated levels of ABCG2 in doxycycline induced sU251MG-V cells led to a diminished accumulation of PpIX and higher light doses were needed to reduce cell viability. By inhibiting the ABCG2 transporter with the efficient and non-toxic ABCG2 inhibitor KO143, PpIX accumulation and PDT efficiency could be strongly enhanced.
Conclusion:
Glioblastoma cells with high ABCG2 expression accumulate less photosensitizer and require higher light doses to be eliminated. Inhibition of ABCG2 during photosensitizer accumulation and irradiation promises to restore full susceptibility of this crucial tumor cell population to photodynamic treatment.
