In silico and in vitro analysis of the role of cowaxanthone as a histone deacetylase inhibitor and apoptosis inducer in human leukemic T-cells

Abstract

Histone deacetylase inhibitors (HDACis) are a class of anticancer agents that have received great attention. There are several of these compounds that are already being used in the clinical phase. However, unwanted side effects to patients are still illustrated. In this study, we aimed to discover a new type of HDACi from a natural agent. A natural xanthone, cowaxanthone, isolated from Garcinia fusca Pierre was selected due to its potential effects on cancer cytotoxicity. In silico docking and in vitro screening activity assays were carried out in order to investigate its role as an HDACi. The cytotoxic effects were also determined by MTT assay against Jurkat and MDA-MB-231 cells and compared to normal Vero cells. In addition, the mode of apoptotic death was preliminarily detected. As a result, cowaxanthone showed an optimum scoring function (docking energy) on all chosen target HDACs in class I (HDACs 2 and 8) and II (HDACs 4 and 7) with binding energies of 105.56, 74.24, 81.00 and 92.88 kcal/mol, respectively. These scores were high and in a similar range to those of standard HDACis, trichostatin A (TSA) and vorinostat (SAHA). In addition, cowaxanthone inhibited HDAC activity in vitro in a dose-dependent manner, in which increasing levels of acetylation of histones H3 and H4 were observed. The anticancer effects of cowaxanthone were clearly indicated in both Jurkat and MDA-MB-231 cells, which less toxic to Vero cells. Moreover, DNA fragmentation, apoptotic bodies and caspase-3, caspase-8 and caspase-9 activation were indicated. In conclusion, our results revealed a novel role of cowaxanthone as an HDACi, in which both classes I and II are inhibited. Apoptotic death was also suggested to be the cowaxanthone cytotoxicity mechanism. © 2018-2020, Rangsit University.