ATO and Gossypol for GSC treatment

ABSTRACT: Glioblastoma is one of the deadliest malignancies worldwide and is virtually incurable due to its highly infiltrative growth and limited sensitivity to conventional treatment by radiochemotherapy. It is hypothesized that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. These cells are characterized by an enhanced DNA repair capacity and expression of stemness marker genes, and elimination of this population might delay or even stop 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 can efficiently target these cancer stem cells and sensitize them to chemotherapeutic drugs. Using tumor sphere lines and primary glioma cells we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the Hh/Notch inhibitor arsenic trioxide (ATO) are capable to synergistically decrease proliferation and induce cell death in combination with the natural cotton derived anticancer agent (-)-Gossypol (Gos). In contrast to GANT in combination with Gos, the ATO/Gos combination also strongly prevented sphere formation and recovery. These synergistic effects were associated with major proteomic changes indicating decreased cell movement, distortion of cell cycle and DNA repair, as well as markedly reduced stemness. Collectively, our data show that ATO and Gos, two drugs that are safe for use in humans, represent a promising targeted therapy approach for the synergistic and specific elimination of glioma stem-like cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Cell Culture

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Florian Bonn  

LAB HEAD: Donat Koegel

PROVIDER: PXD009249 | Pride | 2019-03-13

REPOSITORIES: Pride