ABSTRACT
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response (AU9
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Subject(s)
Humans , Male , Female , Glioblastoma/diagnosis , Glioblastoma/radiotherapy , PTEN Phosphohydrolase/administration & dosage , PTEN Phosphohydrolase/analysis , Biomarkers/analysis , Biomarkers, Tumor/analysis , Chemoradiotherapy, Adjuvant/methods , PTEN Phosphohydrolase/radiation effects , Radiation Tolerance/radiation effects , Phosphatidylinositol 4,5-Diphosphate/analysis , Phosphatidylinositol 4,5-Diphosphate/radiation effects , Adenosine Diphosphate Ribose/analysis , Adenosine Diphosphate Ribose/radiation effectsABSTRACT
The Drosophila phototransduction cascade transforms light into depolarizations that are further shaped by activation of voltage-dependent K+ (Kv) channels. In whole-cell recordings of isolated photoreceptors, we show that light selectively modulated the delayed rectifier (Shab) current. Shab currents were increased by light with similar kinetics to the light-induced current itself (latency approximately 20 ms), recovering to control values with a t(1/2) of approximately 60 s in darkness. Genetic disruption of PLCbeta4, responsible for light-induced PIP(2) hydrolysis, abolished this light-dependent modulation. In mutants of CDP-diaclyglycerol synthase (cds(1)), required for PIP(2) resynthesis, the modulation became irreversible, but exogenously applied PIP(2) restored reversibility. The modulation was accurately and reversibly mimicked by application of PIP(2) to heterologously expressed Shab channels in excised inside-out patches. The results indicate a functionally implemented mechanism of Kv channel modulation by PIP(2) in photoreceptors, which enables light-dependent regulation of signal processing by direct coupling to the phototransduction cascade.
Subject(s)
Drosophila Proteins/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Photoreceptor Cells, Invertebrate/metabolism , Shab Potassium Channels/metabolism , Vision, Ocular/physiology , Animals , Diacylglycerol Cholinephosphotransferase/genetics , Diacylglycerol Cholinephosphotransferase/metabolism , Dose-Response Relationship, Radiation , Drosophila , Drosophila Proteins/radiation effects , Light , Mutant Proteins/genetics , Mutant Proteins/metabolism , Phosphatidylinositol 4,5-Diphosphate/radiation effects , Phospholipase C beta/metabolism , Shab Potassium Channels/radiation effectsABSTRACT
With the aim of examining the response of plant cells to extremely low frequency (ELF) electromagnetic fields (EMF), we investigated the behaviour of the phosphatidylinositol 4,5 bisphosphate (PtdIns 4,5-P(2)) molecule (the precursor of the phosphoinositide signal transduction cascade) by exposing callus cells from Peganum harmala to 50 Hz, 1 gauss EMF for 10 min and by examining the level and the fatty acid composition of PtdIns 4,5-P(2) after the exposure. Our results evidenced a statistically significant decrease in PtdIns 4,5-P(2) concentrations and a different involvement of the constituting fatty acids in the induced breakdown. The manipulation of the lipid-based signalling pathway by phosphoinositide-phospholipase C (PI-PLC) inhibitors (i.e., neomycin, U-73122 and ET-18-OCH(3)) seems to support the hypothesis that, as in animals, also in plants, the cell membrane is the primary impact site of ELF electromagnetic stimulus and that this interaction could probably involve the activation of PI signal transduction pathway including a heterotrimeric G protein.
