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Cancers 2019, 11(3), 350; https://doi.org/10.3390/cancers11030350

Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling

1
Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, 60528 Frankfurt am Main, Germany
2
Radiotherapy and Oncology, Goethe University Hospital, 60590 Frankfurt am Main, Germany
3
Institute of Biochemistry II, Faculty of Medicine, Goethe University Hospital, 60590 Frankfurt am Main, Germany
4
Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany
5
Department of Neurosurgery, Goethe University Hospital, 60528 Frankfurt am Main, Germany
6
German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Received: 28 December 2018 / Revised: 28 February 2019 / Accepted: 7 March 2019 / Published: 12 March 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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Abstract

Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells. View Full-Text
Keywords: cancer stem cells; glioblastoma; Hedgehog; Notch; DNA damage cancer stem cells; glioblastoma; Hedgehog; Notch; DNA damage
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Linder, B.; Wehle, A.; Hehlgans, S.; Bonn, F.; Dikic, I.; Rödel, F.; Seifert, V.; Kögel, D. Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling. Cancers 2019, 11, 350.

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