Abstract B95: Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis.

Abstract

Abstract We synthesized statin hydroxamates (JMF3086, JMF3171, and JMF3173), which are small molecules that simultaneously inhibit histone deacetylases (HDACs) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). These statin hydroxamates were found to be cytotoxic in numerous human cancer cell lines, but not in normal cells, and to induce caspase-dependent apoptosis in HCT116 colon cancer cells. A genome-wide ChIP-on-chip analysis demonstrated that JMF3086 downregulated the expression of inflammatory and stemness genes and upregulated tumor suppressor genes. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) predicted that several of the inflammatory genes were regulated by NF-κB and that the apoptosis-related genes were regulated by NR3C1. The oral administration of statin hydroxamates prevented dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colorectal cancer (CRC) in mice by inhibiting inflammation. JMF3086 and JMF3173 exerted a therapeutic effect in mice with CRC by inducing apoptosis. CRC metastasis to the lungs was inhibited by JMF3086. A positive correlation was detected between the inhibition of HMGR and HDACs and the preventive or therapeutic effects of JMF3086. In addition, the self-renewal and stemness of colorectal cancer stem cells were inhibited by the statin hydroxamates both in vitro and in vivo. Thus, statin hydroxamates show potential as lead compounds for the future development of cancer prevention and treatment. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B95. Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Pei-Ming Yang, Jhih-Bin Chen, Jim-Min Fang, Ching-Chow Chen. Statin hydroxamates, novel inhibitors targeting histone deacetylases and HMG-CoA reductase, suppress colorectal carcinogenesis associated with colitis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B95.