Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta.
BACKGROUND
Glioblastoma (GBM), the most common and aggressive primary brain tumor, is characterized by excessive brain infiltration which prevents the complete surgical resection. These tumors also display treatment non-compliance and responses to standard therapy are invariably transient; consequently, the prognosis barely exceeds 14 months and recurrence is inevitable. Accordingly, several new treatment strategies have been studied. One such option is the use of chloroquine (CQ), a lysosomotropic weak base and renowned antimalarial drug, that has shown promising results in several pre-clinical studies. In this paper, we investigate the efficiency of CQ to hinder the malignant phenotype of GBM, namely extensive proliferation, invasion and radio-resistance.


RESULTS
In cell cycle analysis, proliferation assays and immunofluorescence, CQ treatments halved proliferation of primary cultures from GBM specimens and GBM cell lines (U-373 MG et U-87 MG). Gelatin zymography and Matrigel(TM)-coated transwell invasion assays also revealed a 50 % CQ induced inhibition of MMP-2 activity and GBM invasion. Concomitant treatment with CQ and radiation also radiosensitized GBM cells as shown by an accumulation in the G2/M phase, increased cell death and reduced clonogenic formation. Moreover, radiation-induced invasion was considerably restrained by CQ. We also observe that these effects are owed to CQ-induced inhibition of TGF-β secretion and signaling pathway, a predominant growth factor in GBM progression.


CONCLUSIONS
These results suggest that CQ, alone or as an adjuvant therapeutic, could be used to inhibit the GBM malignant phenotype and could benefit GBM afflicted patients.
Department of Pharmacology, The Health Campus of the Université de Sherbrooke, Sherbrooke, QC, J1H 5 N4, Canada.
Laurent-Olivier
LO
Roy
Department of Surgery, Division of Neurosurgery and Neuro-Oncology, The Health Campus of the Université de Sherbrooke, 12th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada.
Marie-Belle
MB
Poirier
Department of Surgery, Division of Neurosurgery and Neuro-Oncology, The Health Campus of the Université de Sherbrooke, 12th Avenue North, Sherbrooke, QC, J1H 5 N4, Canada. David.Fortin@USherbrooke.ca.
David
D
Fortin
D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059248:Chemoradiotherapy; D002738:Chloroquine / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D016212:Transforming Growth Factor beta; D002738:Chloroquine; D020778:Matrix Metalloproteinase 2
Cellular proliferation and invasion; Chloroquine; Glioblastoma; Radioresistance; Transforming growth factor-beta