title: Antitumor effect of liposomal histone deacetylase inhibitor-lipid conjugates in vitro.
abstract: Histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA), approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma, is a promising new treatment strategy for various cancers. In this study, we hypothesized that a liposomal formulation of HDACI might efficiently deliver HDACI into tumors. To incorporate HDACI efficiently into the liposomal membrane, we synthesized six HDACI-lipid conjugates, in which polyethylene glycol(2000) (PEG(2000))-lipid or cholesterol (Chol) was linked with a potent hydroxamic acid, HDACI, SAHA or K-182, by cleavable linkers, such as ester, carbamide and disulfide bonds. Liposomal HDACI-lipid conjugates were prepared with distearoylphosphatidylcholine (DSPC) and HDACI-Chol conjugate or with DSPC, Chol and HDACI-PEG-lipid conjugates, and their cytotoxicities were evaluated for human cervix tumor HeLa and mouse colon tumor Colon 26 cells. Among the liposomes, liposomal oleyl-PEG(2000)-SAHA conjugated with SAHA and oleyl-PEG(2000) via a carbamate linker showed higher cytotoxicity via hyperacetylation of histone H3 and induction of caspase 3/7 activity. These results suggested that liposomal HDACI-lipid conjugates may be a potential tool for cancer therapy.
authors: Institute of Medicinal Chemistry, Hoshi University, Tokyo 142–8501, Japan. yhattori@hoshi.ac.jp
authors: Yoshiyuki
authors: Y
authors: Hattori
authors: Yasuo
authors: Y
authors: Nagaoka
authors: Manami
authors: M
authors: Kubo
authors: Haruka
authors: H
authors: Yamasaku
authors: Yuta
authors: Y
authors: Ishii
authors: Hiroko
authors: H
authors: Okita
authors: Hiroki
authors: H
authors: Nakano
authors: Shinichi
authors: S
authors: Uesato
authors: Yoshie
authors: Y
authors: Maitani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D009369:Neoplasms; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008055:Lipids; D008081:Liposomes; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D053148:Caspase 3; D053179:Caspase 7; D006655:Histone Deacetylases