Cancer is an increasingly prevalent health problem and remains a major cause of mortality around the world. Despite advances in anti-cancer drug discovery and development in the last few decades, the prognosis for patients with advanced cancers such as colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC) remains largely unchanged. Therefore, there is an ongoing urgent need for novel drugs in the treatment of cancers. Recent development in drug discovery has highlighted the broad pharmacological properties of a key pharmacophore, hydroxamate, although the exact mechanisms remain unclear. In addition, growing evidence showed that histone deacetylases inhibitors (HDACis) have emerged as a powerful new class of anti-tumor therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. We recently demonstrated that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory, anti-angiogenic and anti-tumor activities thorough activating MKP-1, SHP-1 or p53 signaling. On the basis of the strategy of creating multifunctional drugs, a novel series of aliphatic hydroxamate derivatives WMJ-J compounds (WMJ-J-001〜WMJ-J-023) with potent HDACs inhibitory activities were designed and synthesized using WMJ-S-001 as a template. In our preliminary studies, we found that these WMJ-J compounds induced histone 3 acetylation and decreased cell viability in various cancer cell lines. We selected and found that WMJ-J-002 induced cell cycle arrest and apoptosis in HCT116 colorectal cancer cells. These actions were associated with a-tubulin acetylation, tubulin depolymerization, JNK1/2 and p38MAPK phosphorylation, as well as the modulation of p21cip/Waf1, cyclin D1 and survivin. Results from microarray analysis showed that WMJ-J-002 up-regulated 66 microRNAs (miRNAs) in HCT116 cells. Furthermore, WMJ-J-002 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in v/vo. This project aims to explore the underlying mechanisms by which WMJ-J-002 suppress colorectal cancer progression. The causal role of HDACs, protein phosphatases, p53 and miRNAs in WMJ-J-0025 anti-tumor actions will also be established. The central hypothesis of this project is that WMJ-J-002 modulates cell cycle regulators and miRNAs via HDACs inhibition or HDACs-independent mechanisms, which suppresses colorectal cancer progression. Understanding the anti-tumor mechanisms of the novel aliphatic hydroxamate derivatives such as WMJ-J-002 will aid in future development of aliphatic hydroxamate derivatives for cancer treatment.
|Effective start/end date||8/1/16 → 7/31/17|
- Histone deacetylases (HDACs)
- Colorectal cancer
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