Abstract 2353P
Background
It was well known histone deacetylase (HDAC)s act as regulators of cancer progression in various cancer cells, but conventional pan-HDAC inhibitors used for clinical patients have shown the limitations such as low selectivity, high toxicity and low clinical anticancer efficacy. However, HDAC8 has recently been reported to emerge as a new target protein for cancer treatment among HDAC family class I. Against this background, studies have been conducted to discover new HDAC8 selective inhibitors as anti-cancer drug.
Methods
To appreciate the novel HDAC8 selective inhibitors (EC-352H and EC-374H) function as an anti-cancer agent in lymphoma, we investigated the viability of lymphoma cells and tumor growth of xenograft mouse model by EC-352H or EC-374H. The apoptotic mechanism of each drug was studies using immunoblotting assay. And the safety of EC-352H was evaluated through single-dose toxicity study in compliance with the Good Laboratory Practice (GLP) regulations.
Results
In the microarray analysis (GSE12453), HDAC8 was highly expressed in lymphomas compared with normal tissues. In cytotoxicity tests, the IC50 of EC-352H and EC-374H in p53 mutant lymphoma cell (Daudi) was lower than in p53 wild type (WT) lymphoma cells (OCI-Ly3). These results suggest that EC-352H and EC-374H may be more selective inhibitor in p53 mutant lymphoma than in p53 WT lymphoma. Both drugs downregulated the expression of p53 mutant protein through caspase 3-dependent apoptosis, whereas p53 WT protein was highly expressed by EC-352H or EC-374H. In the Daudi xenograft model, 50 mg/kg administration of each drug significantly inhibited tumor growth compared with vehicle-injected mice. Finally, in vivo toxicity study of EC-352H was performed through single-dose oral administration, and approximate lethal dose (ALD) was calculated 500-1000 mg/kg in ICR mice.
Conclusions
EC-352H and EC-374H, novel HDAC8 specific inhibitors, act as anticancer agents and inhibit lymphoma. These can be potential alternatives for overcoming disadvantages of conventional HDAC inhibitors by enhancing HDAC8 selectivity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Eone-Diagnomics.
Disclosure
All authors have declared no conflicts of interest.
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