title: Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells.
abstract: Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia. This complex was further modified with the addition of a cell penetrating peptide, SynB1, for improved cellular uptake and blood-brain barrier penetration. The SynB1-ELP1-dnMAML was examined for its cellular uptake, cytotoxicity, apoptosis, cell cycle inhibition and the inhibition of target genes' expression. SynB1-ELP1-dnMAML inhibited the growth of D54 and U251 cells by inducing apoptosis and cell cycle arrest, especially in the presence of hyperthermia. Hyperthermia increased overall uptake of the polypeptide by the cells and enhanced the resulting pharmacological effects of dnMAML, showing the inhibition of targets of Notch pathway such as Hes-1 and Hey-L. These results confirm that dnMAML is an effective Notch inhibitor and combination with ELP may allow thermal targeting of the SynB1-ELP1-dnMAML complex in cancer cells while avoiding the dangers of systemic Notch inhibition.
authors.affiliation: a Department of Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine , J.J. Strossmayer University of Osijek , Osijek , Croatia.
authors.forename: Teuta
authors.initials: T
authors.lastname: Opačak-Bernardi
authors.affiliation: b Department of Biochemistry , University of Mississippi Medical Center , Jackson , MS , USA.
authors.forename: Jung Su
authors.initials: JS
authors.lastname: Ryu
authors.affiliation: b Department of Biochemistry , University of Mississippi Medical Center , Jackson , MS , USA.
authors.forename: Drazen
authors.initials: D
authors.lastname: Raucher
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004549:Elastin / Q000008:administration & dosage; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D010455:Peptides / Q000008:administration & dosage; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D057846:Cell-Penetrating Peptides; D004268:DNA-Binding Proteins; C430872:MAML1 protein, human; D010455:Peptides; D051880:Receptors, Notch; D014157:Transcription Factors; D004549:Elastin
keywords: Cell penetrating peptide; Notch pathway; anticancer; dnMAML; elastin-like polypeptide