title: A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance.
abstract: Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soo Been
authors.initials: SB
authors.lastname: Park
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: CrystalGenomics, Inc., 5F, Bldg A, Korea Bio Park, Seongnam, Korea.
authors.forename: Sool Ki
authors.initials: SK
authors.lastname: Kwon
authors.affiliation: CrystalGenomics, Inc., 5F, Bldg A, Korea Bio Park, Seongnam, Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Cha
authors.affiliation: CrystalGenomics, Inc., 5F, Bldg A, Korea Bio Park, Seongnam, Korea.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Lee
authors.affiliation: CrystalGenomics, Inc., 5F, Bldg A, Korea Bio Park, Seongnam, Korea.
authors.forename: Seonggu
authors.initials: S
authors.lastname: Ro
authors.affiliation: CrystalGenomics, Inc., 5F, Bldg A, Korea Bio Park, Seongnam, Korea.
authors.forename: Joong Myung
authors.initials: JM
authors.lastname: Cho
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Si Young
authors.initials: SY
authors.lastname: Song
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C572619:N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-loxy)methyl)oct-2-enediamide; D009281:Naphthalenes; D003841:Deoxycytidine; D000093542:Gemcitabine