title: Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists.
abstract: The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.
authors.affiliation: Veterans Affairs (VA) Medical Center, Miami, FL 33125.
authors.forename: Miklos
authors.initials: M
authors.lastname: Jaszberenyi
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Petra
authors.initials: P
authors.lastname: Popovics
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Cai
authors.forename: Irving
authors.initials: I
authors.lastname: Vidaurre
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.forename: Arumugam R
authors.initials: AR
authors.lastname: Jayakumar
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004358:Drug Therapy / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005904:Glial Fibrillary Acidic Protein; D005909:Glioblastoma / Q000188:drug therapy*; D013007:Growth Hormone-Releasing Hormone / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C587256:GH-RH(1-29), desaminotyrosyl(1)-ornithyl(12,21)-alpha-aminobutryic acid(15)-norleucyl(27)-aspartyl(28)-agmatine(29)-; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D064231:Nestin; D010446:Peptide Fragments; C528900:glial fibrillary astrocytic protein, mouse; D004317:Doxorubicin; D013007:Growth Hormone-Releasing Hormone
keywords: peptide analogs; targeted therapy