title: Human glioblastoma stem-like cells accumulate protoporphyrin IX when subjected to exogenous 5-aminolaevulinic acid, rendering them sensitive to photodynamic treatment.
abstract: Glioblastoma (GBM) is the most frequent and lethal primary brain tumor in adults. Despite multimodal therapy combining resection, radio- and alkylating chemotherapy, disease recurrence is universal and prognosis of patients is poor. Glioblastoma stem-like cells (GSC), which can be grown as neurospheres from primary tumors in vitro, appear to be resistant to the established therapies and are suspected to be the driving force for disease recurrence. Thus, efficacy of emerging therapies may depend on targeting GSC. 5-aminolaevulinic acid-mediated photodynamic therapy (5-ALA/PDT) is a promising therapeutic approach in GBM. It utilizes the selective accumulation of the photosensitizer protoporphyrin IX (PPIX) in GBM cells after application of 5-ALA. When exposed to laser light of 635nm wavelength, PPIX initiates a photochemical reaction resulting in the generation of reactive oxygen species, which kill the tumor cells. Whether GSC accumulate PPIX and are sensitive to 5-ALA/PDT is currently unknown. Therefore, human GSC were derived from primary tumors and grown as neurospheres under serum free conditions. When subjected to exogenous 5-ALA, a dose- and time-dependent accumulation of PPIX in GSC was observed by flow cytometry, which varied between individual GSC preparations. Subsequent exposure to laser light of 635nm wavelength substantially killed GSC, whereas treatment with 5-ALA or exposure to laser light only had no effect. LD50 values differed between GSC preparations, but were negatively correlated with PPIX accumulation in GSC. In summary, we report for the first time that glioblastoma stem-like cells accumulate PPIX when subjected to 5-aminolaevulinic acid and are sensitive to 5-aminolaevulinc acid based photodynamic therapy.
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors: Adrian
authors: A
authors: Schimanski
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors: Lara
authors: L
authors: Ebbert
authors: Department of Neurosurgery, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors: Michael C
authors: MC
authors: Sabel
authors: Department of Neuro-Oncology, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Via Giovanni Celoria 11, 20133 Milano, Italy.
authors: Gaetano
authors: G
authors: Finocchiaro
authors: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Katrin
authors: K
authors: Lamszus
authors: Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
authors: Christian
authors: C
authors: Ewelt
authors: Department of Neurosurgery, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors: Nima
authors: N
authors: Etminan
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors: Johannes C
authors: JC
authors: Fischer
authors: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: ruediger.sorg@med.uni-duesseldorf.de.
authors: Rüdiger V
authors: RV
authors: Sorg
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism* / Q000494:pharmacology; D011524:Protoporphyrins / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: 5-aminolaevulinic acid; Cancer stem cells; Glioblastoma; Glioblastoma stem-like cells; Photodynamic therapy; Protoporphyrin IX