Abstract
Abstract Novel therapeutic targets are critical to unravel for recalcitrant malignancies, such as the most common primary brain tumor in adults, glioblastoma (GBM). Heterogeneity remains a hallmark of primary glial brain tumors and therefore targeting several pathways simultaneously is an appropriate approach. Here, we showed that pharmacological activation of the mitochondrial ClpP protease through utilization of the novel imipridone compounds (ONC206 and ONC212) in combination with global (Panobinostat) and selective (romidepsin) HDAC – inhibitors caused synergistic reduction of viability in established and patient-derived xenograft (PDX) cultures of human GBM. This effect occurred independent of TP53 status and was partially mediated by activation of a cell death with apoptotic features accompanied by activation of initiator and effector caspases as well as cleavage of PARP. Consistently, the combination treatment altered the expression of anti-apoptotic and pro-apoptotic Bcl-2 family members, resulting in down-regulation of Bcl-xL and Mcl-1. Knockdown experiments targeting Noxa, BIM, Bcl-xL and Mcl-1 confirmed a functional implication of these proteins in the reduction of cellular viability mediated by the combination treatment. Importantly, knockdown of the ClpP protease significantly rescued the reduction of cellular viability by ClpP activators and the combination treatment, respectively, suggesting critical involvement of this protein. Finally, using a PDX model, we demonstrated that the combination treatment of romidepsin and ONC206 reduced tumor growth more potently than single treatments or vehicle by enhanced reduction of cellular proliferation and pronounced induction of cell death in vivo. Collectively, these observations suggest that the efficacy of HDAC-inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
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