ABSTRACT
BACKGROUND: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). MATERIALS AND METHODS: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. RESULTS: Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CONCLUSION: CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.
Subject(s)
Brain Neoplasms/drug therapy , Convection , Drug Delivery Systems , Glioma/drug therapy , Hydroxamic Acids/therapeutic use , Indoles/therapeutic use , Micelles , Nanoparticles/chemistry , Poloxamer/chemistry , Animals , Cell Death , Cell Line, Tumor , Cell Survival , Disease Models, Animal , Fluorescent Antibody Technique , Humans , Hydroxamic Acids/administration & dosage , Indoles/administration & dosage , Panobinostat , Rats, Inbred F344 , Rats, Wistar , Survival AnalysisABSTRACT
Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Isoquinolines/chemistry , Reactive Oxygen Species/metabolism , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor/methods , Humans , Inhibitory Concentration 50 , Isoquinolines/pharmacology , MCF-7 Cells , Structure-Activity RelationshipABSTRACT
Hypoxia inducible factor-1 (HIF-1) directs the cellular response to low oxygen and plays a key role in tumour survival and growth. Here we use an inhibitor of the HIF-1α/HIF-1ß protein-protein interaction to show the presence of an epigenetically controlled transactivation loop whereby the HIF-1 transcription factor promotes the expression of its own α-subunit in hypoxic cancer cells.
