Pharmacological Mechanisms of the Novel Aliphatic Hydroxamate Derivative Wmj-J in Suppressing Colorectal Cancer Progression: the Role of Phosphatase, Micrornas and Survivin Modulation

Colorectal cancer (CRC) is one of the most prevalent malignancies and the fourth leading cause of cancer deaths worldwide. During the last few decades, the prognosis for patients with advanced CRC remains largely unchanged in spite of the advances in anti-cancer drug discovery and development. It is thus an ongoing urgent need for developing novel therapeutic strategies or agents for cancer intervention. Although the exact mechanisms remain unclear, recent development in drug discovery has highlighted the broad pharmacological properties of a key pharmacophore, hydroxamate. In addition, growing evidence demonstrated 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 and other non-histone protein targets. We recently synthesized and showed that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory, anti-angiogenic and anti-colorectal cancer activities. Base on the strategy of creating multifunctional drugs, we used WMJ-S-001 as a template to design and synthesize another series of aliphatic hydroxamate derivatives WMJ-J compounds displaying potent HDACs inhibitory activities. In our preliminary studies, we found that these WMJ-J compounds induced histone 3 acetylation and decreased cell viability in several colorectal cancer cell lines. We selected and found that WMJ-J-002 induced G2/M phase cell cycle arrest and apoptosis in HCT116 colorectal cancer cells. These actions were associated with α-tubulin acetylation, tubulin depolymerization, as well as survivin down-regulation. Results from microarray analysis showed that WMJ-J-002 up-regulated 66 microRNAs (miRNAs) in HCT116 cells. Among these 66 miRNAs, eight miRNAs including miR-320a are down-regulated with tumor progression in CRC patients according to the data of The Cancer Genome Atlas (TCGA) project. Moreover, miR-320a target neurophilin-1 (NRP-1) was reduced in HCT116 cells exposed to WMJ-J-002. Furthermore, WMJ-J-002 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. This project aims to explore the underlying mechanisms by which WMJ-J-002 suppress colorectal cancer progression. The causal role of HDACs and miRNAs in WMJ-J-002’ anti-tumor actions will also be established. The central hypothesis of this project is that WMJ-J-002 modulates miRNAs, NRP-1 and survivin via HDACs inhibition or HDACs-independent mechanisms, leading to the suppression of colorectal cancer progression. Understanding the anti-tumor mechanisms of the novel multifunctional aliphatic hydroxamate derivatives such as WMJ-J-002 will aid in future development of aliphatic hydroxamate derivatives for cancer treatment.