Figure 8.

Schematic diagram of two main targets of the combination treatment. Topo II and HDAC1 are known to interact with each other and modify each other’s activity. CI-994 and etoposide can pass through cell membranes using transporters and/or passive diffusion. CI-994 enters the cell, inhibits HDAC1 enzyme activity and increases histone acetylation, therefore activating cleaved Parp. CI-994 also reduced C-Myc, which was more effective in combination treatment with etoposide. CI-994 can also increase γ–H2AX expression. Etoposide increases γ-H2AX expression, which not only increases cleaved Parp levels but also decreases Survivin levels. The action of each of these drugs through the regulation of Topo II and Ac-H3 synergistically increases cleaved Parp levels and cleaved Caspase-3 levels, leading to the apoptosis of AT/RT cells.