title: Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo.
abstract: Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 µM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects of honokiol were associated with a significant reduction in the viability of NSCLC cells. Concomitant treatment of cells with a proteasome inhibitor, MG132, prevented honokiol-induced degradation of class I HDACs, suggesting that honokiol reduced the levels of HDACs in NSCLC cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of NSCLC cells. Treatment of A549 and H1299 cells with honokiol resulted in an increase in G 1 phase arrest, and a decrease in the levels of cyclin D1, D2 and cyclin dependent kinases. Further, administration of honokiol by oral gavage significantly inhibited the growth of subcutaneous A549 and H1299 tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Singh
authors.forename: Ram
authors.initials: R
authors.lastname: Prasad
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001980:Bronchi / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D017705:Lignans; D046988:Proteasome Endopeptidase Complex; D014635:Valproic Acid; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C012589:trichostatin A