ABSTRACT
Glioblastoma (GBM) is the most frequent brain cancer and more lethal than other cancers. Characteristics of this cancer are its high drug resistance, high recurrence rate and invasiveness. Invasiveness in GBM is related to overexpression of matrix metalloproteinases (MMPs) which are mediated by wnt/ß-catenin and induced by the activation of signaling pathways extracellularly activated by the cytokine neuroleukin (NLK) in cancer stem cells (CSC). Therefore, in this work we evaluated the effect of the tetrose saccharide, erythrose (Ery), a NLK inhibitor of invasiveness and drug sensitization in glioblastoma stem cells (GSC). GSC were obtained from parental U373 cell line by a CSC phenotype enrichment protocol based on microenvironmental stress conditions such as hypoxia, hipoglycemia, drug exposition and serum starvation. Enriched fraction of GSC overexpressed the typical markers of brain CSC: low CD133+ and high CD44; in addition, epithelial to mesenchyme transition (EMT) markers and MMPs were increased several times in GSC vs. U373 correlating with higher invasiveness, elongated and tubular mitochondrion and temozolomide (TMZ) resistance. IC50 of Ery was found at nM concentration and at 24 h induced a severe diminution of EMT markers, MMPs and invasiveness in GSC. Furthermore, the phosphorylation pattern of NLK after Ery exposition also was affected. In addition, when Ery was administered to GSC at subIC50, it was capable of reverting TMZ resistance at concentrations innocuous to non-tumor cancer cells. Moreover, Ery added daily induced the death of all GSC. Those findings indicated that the phytodrug Ery could be used as adjuvant therapy in GBM.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/genetics , Tetroses/metabolism , Tetroses/pharmacology , Tetroses/therapeutic use , Cell Line, Tumor , Temozolomide/therapeutic use , Drug Resistance, Neoplasm , Brain Neoplasms/pathology , Neoplastic Stem Cells/pathology , Protein Serine-Threonine Kinases/metabolismSubject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Tetroses/therapeutic use , Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Erythritol/analogs & derivatives , Ethylamines/administration & dosage , Ethylamines/therapeutic use , Female , Gastrointestinal Neoplasms/drug therapy , Hodgkin Disease/drug therapy , Humans , Injections, Intravenous , Leukemia, Lymphoid/drug therapy , Lung Neoplasms/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Male , Sulfonic Acids/administration & dosage , Sulfonic Acids/therapeutic use , Tetroses/administration & dosage , Urogenital Neoplasms/drug therapyABSTRACT
A series of erythrose, ribose, and substituted pyrrolidine containing 2,4-thiazolidinediones were synthesized. Among them, thirteen unsaturated thiazolidinediones, six saturated thiazolidinediones and two unsaturated malonates were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. On the basis of the in vitro activity, 5-[4-[2-(1-benzyl-3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione 24b was selected as the candidate for further pharmacological studies.