Discovery Of Polyoxometalate-based HDAC Inhibitors With Profound Anticancer Activity In Vitro And In Vivo

Histone deacetylase inhibitors (HDACIs) are promising anticancer agents. In our foregoing study, we screened and identified novel HDACIs from a polyoxometalate (POM) library by using a cell-based system containing the p21 gene promoter reporter that is regulated by histone acetylation-deacetylation modifications. We obtained 13 positive POM compounds that were able to upregulate p21 promoter activity. In this thesis, we further study 5 compounds, PAC-320, a new tri-organic-tin-substitute germanotungstate, displayed the highest extracellular inhibitory activity among the positive POMs. Meanwhile, crystal structure of PAC-320 was characterized by X-ray crystallography and stability studies of PAC-320 were carried out by UV spectrum, CV and TG. Stability studies suggested that PAC-320 could stably exist under physiological conditions. We further showed that PAC-320 possessed a strong inhibitory effect to intracellular HDAC activity. More significantly, PAC-320 inhibited the growth of a variety of cancer cells, and exhibited remarkable anticancer effect in a hepatocarcinoma H22 cell mice model. Thus, our data validated that the new POM compound PAC-320 had the anticancer competency both in vitro and in vivo with little harm to the normal growth of the cells and animals. This study revealed, for the first time, that the HDAC inhibitory activity is a mechanism by which POMs exert their anticancer effect.