Antitumor Effect of Liposomal Histone Deacetylase Inhibitor-Lipid Conjugates in Vitro

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概要

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• 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 glycol2000 (PEG2000)-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-PEG2000-SAHA conjugated with SAHA and oleyl-PEG2000 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.

著者

• HATTORI Yoshiyuki

  Institute of Medicinal Chemistry, Hoshi University

• Maitani Yoshie

  Institute Of Medicinal Chemistry Hoshi University

• Hattori Yoshiyuki

  Institute Of Medicinal Chemistry Hoshi University

• Nagaoka Yasuo

  Faculty Of Chemistry Materials And Bioengineering Kansai University

• Uesato Shinichi

  Faculty Of Chemistry Materials And Bioengineering Kansai University

• Kubo Manami

  Institute of Medicinal Chemistry, Hoshi University

• Yamasaku Haruka

  Institute of Medicinal Chemistry, Hoshi University

• Ishii Yuta

  Faculty of Chemistry, Materials and Bioengineering, Kansai University

• Okita Hiroko

  Faculty of Chemistry, Materials and Bioengineering, Kansai University

• Nakano Hiroki

  Faculty of Chemistry, Materials and Bioengineering, Kansai University

• UESATO Shinichi

  Faculty of Chemistry, Materials and Bioengineering, Kansai University

• Nagaoka Yasuo

  Faculty of Chemistry, Materials and Bioengineering, Kansai University

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