Oncotarget

Priority Research Papers:

BH3-mimetics and BET-inhibitors elicit enhanced lethality in malignant glioma

Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Marc-Eric Halatsch, M. Andrew Westhoff, Georg Karpel-Massler and Markus D. Siegelin _

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Oncotarget. 2017; 8:29558-29573. https://doi.org/10.18632/oncotarget.16365

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Abstract

Chiaki Tsuge Ishida1, Elena Bianchetti1, Chang Shu1, Marc-Eric Halatsch2, M. Andrew Westhoff3, Georg Karpel-Massler2 and Markus D. Siegelin1

1 Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, USA

2 Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany

3 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany

Correspondence to:

Markus D. Siegelin, email:

Keywords: apoptosis, BH3-mimetics, brain cancer, c-myc, Bcl-xL

Received: January 09, 2017 Accepted: February 08, 2017 Published: March 18, 2017

Abstract

Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies. In vivo experiments were performed in a glioblastoma xenograft model. Single treatments with JQ1 and OTX015 had only moderate effects on the reduction of cellular viability. However, the combination treatment of BH3-mimetics along with JQ1 or OTX015 resulted in a highly synergistic reduction of cellular viability in a broad range of different model systems of malignant glioma. Similarly, knockdown of c-myc sensitized glioma cells for ABT263 mediated cell death. The enhanced loss of cellular viability in the combination treatment was mediated by activation of apoptosis with dissipation of mitochondrial membrane potential and caspase cleavage. The combination treatment led to a modulation of anti- and pro-apoptotic Bcl-2 family members with an increase in pro-apoptotic Noxa mediated by ATF4. Small interfering RNA mediated knockdown of Bak and Noxa protected glioma cells from ABT263/JQ1 mediated apoptosis. Finally, the combination treatment of ABT263 and OTX015 resulted in a regression of tumors and a significantly smaller tumor size as compared to single or vehicle treated tumors. Thus, these results warrant clinical testing for the drug combination of BH3-mimetics along with bromodain protein inhibitors.


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