title: Histone deacetylase inhibitors enhance the apoptotic activity of insulin-like growth factor binding protein-3 by blocking PKC-induced IGFBP-3 degradation.
abstract: Overexpression of insulin-like growth factor binding protein (IGFBP)-3 induces apoptosis of cancer cells. However, preexisting resistance to IGFBP-3 could limit its antitumor activities. This study characterizes the efficacy and mechanism of the combination of recombinant IGFBP-3 (rIGFBP-3) and HDAC inhibitors to overcome IGFBP-3 resistance in a subset of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells. The effects of the combination of rIGFBP-3 and a number of HDAC inhibitors on cell proliferation and apoptosis were assessed in vitro and in vivo by using the MTT assay, a flow cytometry-based TUNEL assay, Western blot analyses and the NSCLC xenograft tumor model. Combined treatment with HDAC inhibitors and rIGFBP-3 had synergistic antiproliferative effects accompanied by increased apoptosis rates in a subset of NSCLC and HNSCC cell lines in vitro. Moreover, combined treatment with depsipeptide and rIGFBP-3 completely suppressed tumor growth and increased the apoptosis rate in vivo in H1299 NSCLC xenografts. Evidence suggests that HDAC inhibitors increased the half-life of rIGFBP-3 protein by blocking protein kinase C (PKC)-mediated phosphorylation and degradation of rIGFBP-3. In addition, combined treatment of IGFBP-3 with an HDAC inhibitor facilitates apoptosis through upregulation of rIGFBP-3 stability and Akt signaling inhibition. The ability of HDAC inhibitors to decrease PKC activation may enhance apoptotic activities of rIGFBP-3 in NSCLC cells in vitro and in vivo. These results indicated that combined treatment with HDAC inhibitor and rIGFBP-3 could be an effective treatment strategy for NSCLC and HNSCC with highly activated PKC.
authors.affiliation: Laboratory of Preventive Pharmacy, College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Oh
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Whang
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Han
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Ki-Hoon
authors.initials: KH
authors.lastname: Song
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.forename: Yeul Hong
authors.initials: YH
authors.lastname: Kim
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D014158:Transcription, Genetic / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D011493:Protein Kinase C