monensin and Glioblastoma

Topics: Adult; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Induced Pluripotent Stem Cells; Monensin; Organoids; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Microenvironment

Glioblastoma is characterized by the extensive vascularization with poor prognosis. Targeting both tumor cell and angiogenesis may present an effective therapeutic strategy for glioblastoma. Monensin, a polyether ionophore antibiotic, has been recently recognized as promising anticancer drug candidate due to its potent and selective anti-tumor activities. However, little is known on the effects of monensin on tumor angiogenesis. In this work, we investigated the effects and underlying mechanisms of monensin on glioblastoma angiogenesis and growth. We show that monensin at nanomolar concentrations inhibits early stages of capillary network formation of glioblastoma endothelial cell. Monensin inhibited multiple endothelial cellular events, including migration, growth and survival, without affecting adhesion to Matrigel. We further demonstrate that monensin acts on endothelial cells via suppressing VEGFR- and EGFR-mediated signaling pathways. Monensin also inhibits proliferation and induces apoptosis in a panel of glioblastoma cells. However, monensin is more effective in targeting endothelial cells than tumor cells. Using glioblastoma growth xenograft mice model, we show that monensin at tolerable dose effectively inhibits glioblastoma growth. Of note, there is a significant decreased tumor vascularization from monensin-treated mice. Our work clearly demonstrates the anti-angiogenic activity of monensin and its ability in suppressing multiple tyrosine kinase receptor-mediated pathways. Our findings suggest that is a useful addition to the treatment armamentarium for glioblastoma.

Topics: Angiogenesis Inhibitors; Animals; Brain Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Glioblastoma; Humans; Mice, Nude; Monensin; Neovascularization, Pathologic; Receptors, Growth Factor; Signal Transduction

Autophagy is a lysosome-dependent cellular catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. Reduction of autophagy activity has been shown to lead to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. To explore the mechanism of autophagy and identify small molecules that can activate it, we developed a series of high-throughput image-based screens for small-molecule regulators of autophagy. This series of screens allowed us to distinguish compounds that can truly induce autophagic degradation from those that induce the accumulation of autophagosomes as a result of causing cellular damage or blocking downstream lysosomal functions. Our analyses led to the identification of eight compounds that can induce autophagy and promote long-lived protein degradation. Interestingly, seven of eight compounds are FDA-approved drugs for treatment of human diseases. Furthermore, we show that these compounds can reduce the levels of expanded polyglutamine repeats in cultured cells. Our studies suggest the possibility that some of these drugs may be useful for the treatment of Huntington's and other human diseases associated with the accumulation of misfolded proteins.

Topics: Autophagy; Calcium Channel Blockers; Cell Line, Tumor; Drug Evaluation, Preclinical; Fluspirilene; Glioblastoma; Green Fluorescent Proteins; Humans; Intracellular Membranes; Loperamide; Microtubule-Associated Proteins; Mycotoxins; Peptides; Phagosomes; Phosphatidylinositol Phosphates; Pimozide; Protein Kinases; Recombinant Fusion Proteins; Sirolimus; Small Molecule Libraries; TOR Serine-Threonine Kinases; Trifluoperazine; Zinc Fingers