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: Yoshiyuki Hattori, Yasuo Nagaoka, Manami Kubo, Haruka Yamasaku, Yuta Ishii, Hiroko Okita, Hiroki Nakano, Shinichi Uesato, Yoshie Maitani
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 59 Issue 11 Pg. 1386-92 ( 2011) ISSN: 1347-5223 [Electronic] Japan
• PMID: 22041075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Lipids
• Liposomes
• Phosphatidylcholines
• Polyethylene Glycols
• Cholesterol
• 1,2-distearoyllecithin
• Caspase 3
• Caspase 7
• Histone Deacetylases

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cholesterol (chemistry)
• Histone Deacetylase Inhibitors (chemistry)
• Histone Deacetylases (chemistry, metabolism)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (chemistry)
• Lipids (chemistry)
• Liposomes (chemistry)
• Mice
• Neoplasms
• Phosphatidylcholines (chemistry)
• Polyethylene Glycols (chemistry)