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.

Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs

“…The possible mechanism for the comparable or even further enhanced efficacy in histone acetylation is that POEG- b -PSAHA protected the hydroxamic acid of SAHA from hydrolysis and pharmacologically active SAHA was slowly released from the polymer over a prolonged period of time. On the other hand, free SAHA with unprotected hydroxamic acid may be subjected to rapid metabolic conversion to inactive metabolites, SAHA-glucuronide and 4-anilino-4-oxobutanoic acid (Hattori et al, 2011).…”

Synthesis and Biological Evaluation of 1-(2-Aminophenyl)-3-arylurea Derivatives as Potential EphA2 and HDAC Dual Inhibitors

“…15,16) HDAC inhibitors have been applied to treatment of human cancers. 17,18) Zolinza (vorinostat, SAHA) was approved by the Food and Drug Administration (FDA) for the treatment of advanced cutaneous T-cell lymphoma (CTCL). 19) A benzamide HDAC inhibitor, MS275, is reported to be a selective HDAC inhibitor targeting class I HDACs, which is a moderately potent HDAC inhibitor in phase II clinical trial.…”

Application Potential of Liposomal Delivery Systems Prepared by Lipids Extracted from E. coli Cultures

“…Recently, liposomes have gained potential interest in the field of biotechnology therapeutics as delivery systems for recombinant proteins, antisense oligonucleotides and cloned genes. With the recent development in the field, several companies are actively engaged in expansion and evaluation of liposome products for anticancer, antifungal therapy and for prophylaxis therapy [7][8][9][10][11][12][13][14][15]. It is demonstrated that liposomes have potential impact in submiocron and nano-scale reaction engineering.…”