HDAC inhibition amplifies gap junction communication in neural progenitors: Potential for cell-mediated enzyme prodrug therapy

• Published in: Experimental cell research Vol. 313; no. 13; pp. 2958 - 2967
• Main Authors: Khan, Zahidul, Akhtar, Monira, Asklund, Thomas, Juliusson, Bengt, Almqvist, Per M., Ekström, Tomas J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2007; Elsevier BV
• Subjects: 4-Phenylbutyrate; 60 APPLIED LIFE SCIENCES; BIOLOGICAL RADIATION EFFECTS; Bystander effect; Cell Communication - drug effects; Cell Differentiation; Cell Line; Cell Proliferation; Cellular biology; Connexin 43; Connexin 43 - analysis; Connexin 43 - metabolism; Drug Delivery Systems; Drug therapy; Enzyme Inhibitors - pharmacology; ENZYMES; Gap junction; Gap Junctions - chemistry; Gap Junctions - drug effects; Gene expression; GENE THERAPY; GLIOMAS; Histone Deacetylase Inhibitors; Histone deacetylases; Humans; Hydroxamic Acids - pharmacology; INHIBITION; Inhibitor drugs; Medicin och hälsovetenskap; Molecular biology; MOLECULAR WEIGHT; Neural progenitor cell; Neurons; Neurons - enzymology; Neurons - transplantation; Phenylbutyrates - pharmacology; Prodrugs - administration & dosage; Stem Cell Transplantation; Stem Cells - enzymology; Neural progenitor cell; Connexin 43; Gene therapy; Bystander effect; Histone deacetylases; 4-Phenylbutyrate; Gap junction
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2007.05.004

Enzyme prodrug therapy using neural progenitor cells (NPCs) as delivery vehicles has been applied in animal models of gliomas and relies on gap junction communication (GJC) between delivery and target cells. This study investigated the effects of histone deacetylase (HDAC) inhibitors on GJC for the purpose of facilitating transfer of therapeutic molecules from recombinant NPCs. We studied a novel immortalized midbrain cell line, NGC-407 of embryonic human origin having neural precursor characteristics, as a potential delivery vehicle. The expression of gap junction protein connexin 43 (C×43) was analyzed by western blot and immunocytochemistry. While C×43 levels were decreased in untreated differentiating NGC-407 cells, the HDAC inhibitor 4-phenylbutyrate (4-PB) increased C×43 expression along with increased membranous deposition in both proliferating and differentiating cells. Simultaneously, Ser 279/282-phosphorylated form of C×43 was declined in both culture conditions by 4-PB. The 4-PB effect in NGC-407 cells was verified by using HNSC.100 human neural progenitors and Trichostatin A. Improved functional GJC is of imperative importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds. We show here an enhancement by 4-PB, of the functional GJC among NGC-407 cells, as well as between NGC-407 and human glioma cells, as indicated by increased fluorescent dye transfer.