Figure 2.

Schematic presentation of EDO-S101 DNA alkylating and HDAC inhibitory role and synergistic effect with bortezomib, and the consequences for the cell. EDO-S101 causes DNA alkylation and histone/protein acetylation due to histone deacetylases (HDAC) inhibitory activity. DNA alkylation leads to the induction of double strand breaks in the DNA, which is potentiated by the vulnerability of the DNA to alkylation due to opened chromatin structure and increased transcriptional activity. The DNA damage and increased transcription of cell cycle inhibitors together with inhibition of cell cycle inhibitors (p21) degradation by bortezomib leads to S-phase arrest. Further, transcriptional activation leads to accumulation of polyubiqitinated proteins dedicated for proteasomal degradation which in turn is blocked by bortezomib. Accumulation of polyubiquitinated proteins causes ER stress which unresolved leads to apoptosis. Intracellular effects are summarized in the table below.