ABSTRACT
PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
Subject(s)
Carbazoles/administration & dosage , Carbazoles/pharmacology , Chromatin/drug effects , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/pharmacology , Neuroblastoma/drug therapy , Panobinostat/administration & dosage , Panobinostat/pharmacology , Animals , Drug Combinations , Drug Evaluation, Preclinical , Mice , Tumor Cells, CulturedABSTRACT
BACKGROUND: University students are expressing an increased need for mental health support. Mindfulness-based interventions (MBIs) are being integrated into university stress-reduction programmes globally. We conducted a comprehensive systematic review and meta-analysis of randomised controlled trials (RCTs) assessing MBI effects on university students' mental and physical health. METHODS: We searched nine databases, including grey literature and trial registries. Two independent reviewers extracted data following a prospective public protocol. RESULTS: Fifty-one RCTs were included. In comparison with passive controls, and when measured shortly after intervention completion, MBIs improve distress, anxiety, depression, well-being, rumination, and mindfulness with small to moderate effect sizes, with no benefit found for blood pressure, sleep, life satisfaction, resilience, worry, and thought suppression. Evidence for self-compassion is inconclusive. Effects last beyond three months for distress and mindfulness, with no data on other outcomes. Compared with active control groups, MBIs significantly improve distress and state anxiety, but not mindfulness, depression, well-being, affect, trait anxiety, or emotion regulation. Results were robust to adjustment for multiple testing, but RCTs' risk of bias is generally high. Moderator analyses did not find differential intervention effects according to intervention duration, delivery mode, or sub-populations. CONCLUSIONS: MBIs may be helpful to students but higher-quality research is needed.