title: Induction of brain tumor stem cell apoptosis by FTY720: a potential therapeutic agent for glioblastoma.
abstract: FTY720 is a sphingosine analogue that down regulates expression of sphingosine-1-phosphate receptors and causes apoptosis of multiple tumor cell types, including glioma cells. This study examined the effect of FTY720 on brain tumor stem cells (BTSCs) derived from human glioblastoma (GBM) tissue. FTY720 treatment of BTSCs led to rapid inactivation of ERK MAP kinase, leading to upregulation of the BH3-only protein Bim and apoptosis. In combination with temozolomide (TMZ), the current standard chemotherapeutic agent for GBM, FTY720 synergistically induced BTSC apoptosis. FTY720 also slowed growth of intracranial xenograft tumors in nude mice and augmented the therapeutic effect of TMZ, leading to enhanced survival. Furthermore, the combination of FTY720 and TMZ decreased the invasiveness of BTSCs in mouse brains. FTY720 is known to cross the blood-brain barrier and recently received Food and Drug Administration approval for treatment of relapsing multiple sclerosis. Thus, FTY720 is an excellent potential therapeutic agent for treatment of GBM.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Estrada-Bernal
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Palanichamy
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray Chaudhury
authors.forename: James R
authors.initials: JR
authors.lastname: Van Brocklyn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001932:Brain Neoplasms / Q000188:drug therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D060828:Induction Chemotherapy; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011409:Propylene Glycols; D011518:Proto-Oncogene Proteins; D049349:Receptors, Lysosphingolipid; D003606:Dacarbazine; D048049:Extracellular Signal-Regulated MAP Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D000077204:Temozolomide