title: Valproic acid induced differentiation and potentiated efficacy of taxol and nanotaxol for controlling growth of human glioblastoma LN18 and T98G cells.
abstract: Glioblastoma shows poor response to current therapies and warrants new therapeutic strategies. We examined the efficacy of combination of valproic acid (VPA) and taxol (TX) or nanotaxol (NTX) in human glioblastoma LN18 and T98G cell lines. Cell differentiation was manifested in changes in morphological features and biochemical markers. Cell growth was controlled with down regulation of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NF-κB), phospho-Akt (p-Akt), and multi-drug resistance (MDR) marker, indicating suppression of angiogenic, survival, and multi-drug resistance pathways. Cell cycle analysis showed that combination therapy (VPA and TX or NTX) increased the apoptotic sub G1 population and apoptosis was further confirmed by Annexin V-FITC/PI binding assay and scanning electron microscopy. Combination therapy caused activation of caspase-8 and cleavage of Bid to tBid and increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF). Upregulation of calpain and caspases (caspase-9 and caspase-3) and substrate degradation were also detected in course of apoptosis. The combination of VPA and NTX most effectively controlled the growth of LN18 and T98G cells. Therefore, this combination of drugs can be used as an effective treatment for controlling growth of human glioblastoma cells.
authors.affiliation: Department of Pathology, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Roy Choudhury
authors.forename: Surajit
authors.initials: S
authors.lastname: Karmakar
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D014635:Valproic Acid; D045304:Cytochromes c; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D017239:Paclitaxel