Artikel
Combined inhibition of mitochondrial matrix chaperones and Bcl-xL yields synthetic lethality in glioma
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Veröffentlicht: | 9. Juni 2017 |
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Gliederung
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Objective: We show that combined targeting of the mitochondrial Hsp90 chaperone network and inhibition of the anti-apoptotic Bcl-2 family member Bcl-xL induces synthetic lethality in human gliomas.
Methods: The biological and molecular effects of a combined treatment with the Bcl-xL inhibitor ABT263 and the mitochondrial Hsp90 chaperone inhibitor Gamitrinib-TPP were examined in different pre-clinical glioma models including primary cultures, glioma stem-like cells in vitro and multiple human patient-derived orthotopic glioblastoma xenografts (PDX) in vivo.
Results: Combined treatment with ABT263 and Gamitrinib-TPP yields a synergistic anti-proliferative and pro-apoptotic activity. On the molecular level, this response is mediated by a strong induction of endoplasmic reticulum-stress which was characterized by an increased activation of activating transcription factor 4 through a PERK-dependent mechanism and subsequent up-regulation of pro-apoptotic Noxa. In vivo, the combination therapy lead to a significant prolongation of survival in two orthotopic patient-derived xenograft models of glioblastoma.
Conclusion: Combined inhibition of mitochondrial matrix chaperones and Bcl-xL represents a promising new therapeutic strategy for the treatment of gliomas.