TY  - JOUR
A1  - Linder, Benedikt
A1  - Wehle, Andrej
A1  - Hehlgans, Stephanie
A1  - Bonn, Florian
A1  - Đikić, Ivan
A1  - Rödel, Franz
A1  - Seifert, Volker
A1  - Kögel, Donat
T1  - Arsenic trioxide and (−)-gossypol synergistically target glioma stem-like cells via inhibition of hedgehog and notch signaling
T2  - Cancers
N2  - 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.
KW  - cancer stem cells
KW  - glioblastoma
KW  - Hedgehog
KW  - Notch
KW  - DNA damage
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48809
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-488098
SN  - 2072-6694
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
VL  - 11
IS  - 3, Art. 350
SP  - 1
EP  - 22
PB  - MDPI
CY  - Basel
ER  -