title: Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines.
abstract: The antitumor activity of histone deacetylase inhibitors (HDACI) on multidrug-resistant sarcoma cell lines has not been previously described. Treatment of multidrug-resistant sarcoma cell lines with HDACI PCI-24781 resulted in dose-dependent accumulation of acetylated histone, p21 and poly(ADP-ribose)polymerase (PARP) cleavage products. Growth of these cell lines was inhibited by PCI-24781 at IC(50) of 0.43 to 2.7. When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 reverses drug resistance in all four multidrug-resistant sarcoma cell lines and synergizes with chemotherapeutic agents to enhance caspase-3/-7 activity. Expression of RAD51 (a marker for DNA double-strand break repair) was inhibited and the expression of GADD45α (a marker for growth arrest and DNA-damage) was induced by PCI-24781 in multidrug-resistant sarcoma cell lines. In conclusion, HDACI PCI-24781 synergizes with chemotherapeutic drugs to induce apoptosis and reverses drug resistance in multidrug-resistant sarcoma cell lines.
authors.affiliation: Department of Orthopaedic Surgery, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China. yangcaom@gmail.com
authors.forename: Cao
authors.initials: C
authors.lastname: Yang
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.forename: Kirkham B
authors.initials: KB
authors.lastname: Wood
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Schwab
authors.forename: Xianzhe
authors.initials: X
authors.lastname: Liu
authors.forename: Henry
authors.initials: H
authors.lastname: Mankin
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000097642:GADD45 Proteins
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001572:Benzofurans; D020169:Caspases; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C512352:abexinostat