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Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta

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Summary

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 MatrigelTM-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. Conclusion 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.

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Acknowledgments

We thank Pr Claire Dubois for kindly providing the 2× SYBR Green qPCR Mastermix and PAI-1 primers as well as for helpful discussions. We also thank Pr. Jean-François Beaulieu for the gift of the immunofluorescence antibodies and Dr. Leonid Volkov for his technical assistance during flow cytometry experiments. All culture media were generously provided by Wisent Bioproducts.

Grant support

This work was supported by the National Bank research chair on the treatment of brain tumors as well as by the Fondation du CHUS and the Fondation de l’université de Sherbrooke.

Conflict of interest

The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, The Health Campus of the Université de Sherbrooke, Sherbrooke, QC, J1H 5 N4, Canada

    Laurent-Olivier Roy

  2. 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 Poirier & David Fortin

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Correspondence to David Fortin.

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Roy, LO., Poirier, MB. & Fortin, D. Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta. Invest New Drugs 33, 1020–1031 (2015). https://doi.org/10.1007/s10637-015-0275-x

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