Abstract
The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.
Highlights
Patients suffering from glioblastoma (GBM), the most common primary malignant brain tumor, still require more efficient therapies to extend the so far unsatisfying overall survival between twelve to fifteen months [1,2]
This occurred in a similar fashion, suggesting that the genetic make-up of these tumor cells likely does not contribute to the efficacy of the combination treatment in light of the fact that U87 are wild type TP53, whereas in contrast LN229 are mutated
These results suggest that the combination treatment of global histone deacetylase (HDAC) inhibitors in combination with TRAP1 inhibitors are effective in reducing the viability of a variety of GBM cells, likely to be irrespective of TP53 status
Summary
Patients suffering from glioblastoma (GBM), the most common primary malignant brain tumor, still require more efficient therapies to extend the so far unsatisfying overall survival between twelve to fifteen months [1,2]. What remains clear is that glioblastomas are amongst the most heterogeneous cancers and this pivotal observation clearly suggests that drug combination treatments are likely the key to achieve a better prognosis for this disease [1,2,3]. Proceeding with this premise, we have conducted a high-throughput drug screen and found that mitochondrial matrix chaperone inhibitors that are in preparation for clinical testing cause synthetic lethality in the presence of selective or global histone deacetylase (HDAC) inhibitors in cancer cells [4]. Represented by the lead compound gamitrinib (GTPP) mitochondrial matrix chaperone inhibitors have shown anti-cancer activity in several tumor model systems, including prostate cancer, colon cancer, lymphoma, leukemia and glioblastoma [5,6,7]. With regards to the underlying mechanisms, gamitrinib was linked to mitochondrial permeability related cell death akin to its related predecessor, the Hsp inhibitor peptide shepherdin [8,9], which interferes with both cytosolic and mitochondrial
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