Background and Aims: Colorectal cancer (CRC) is an important cancer with rising annual incidence worldwide, leading to significant morbidity and mortality. The addition of new anti-CRC drugs significantly improves treatment outcome, indicating that it is crucial to develop new drugs. Chemoprevention is another important approach to reduce cancer-related mortality. We first demonstrated statins with a carboxylic acid-containing long chain inhibiting histone deacetylase (HDAC) activity. To further improve their HDAC inhibition, we designed and synthesized three statin hydroxamates (JMF3086, JMF3171 and JMF3173) that potently inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and histone deacetylases (HDACs) simultaneously. Their preventive and therapeutic effects on CRC were investigated.
Methods: The in vitro anticancer activity was evaluated in human cancer cells. Molecular mechanisms were investigated using genome-wide ChIP-on-chip, Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). Anti-inflammation was examined by Dextran sulfate sodium (DSS)-induced acute colitis in mice. Prevention or therapy for CRC was examined by AOM/DSS mouse model. Anti-metastasis was examined by splenic and tail vein injected mouse models, and colorectal cancer stem cells were generated to investigate the inhibition of stemness.
Results: Statin hydroxamates were effective to inhibit a variety of human cancer cells. ChIP-on-chip analysis demonstrated the down-regulation of inflammatory and stemness genes and up-regulation of tumor suppressor genes. GO and IPA predicted the regulatory role of NF-kB in inflammatory genes and NR3C1 in apoptosis-related genes. The oral administration of JMF3086 prevented DSS-induced colitis and AOM/DSS-induced CRC in mice by inhibiting inflammation. Statin hydroxamates exerted a therapeutic effect in CRC mice by inducing apoptosis. CRC metastasis to the livers and lungs and the propagation of CRC stem cells in vivo were also inhibited by JMF3086. The efficacy of JMF3086 was superior to the combination of lovastatin and SAHA (HDAC inhibitor) with less toxicity.
Conclusions: Statin hydroxamates with dual inhibition on HMGR and HDACs show great preclinical efficacy in prevention and treatment of CRC through inhibiting inflammation and inducing apoptosis.
Citation Format: Tzu-Tang Wei, Yi-Ting Lin, Yu-Chin Lin, Ching-Chow Chen. Small molecules targeting HMGR and HDAC in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A92.
- ©2015 American Association for Cancer Research.