Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51
Figure 6
A proposed model of molecular mechanisms underlying the cooperative induction of apoptosis by HDACIs and DNA damaging agents in AML cells.
HDACIs suppress the transcript and protein levels of the transcription factor gene E2F1, leading to decreased expression of BRCA1, CHK1, and RAD51. Decreased expression of BRCA1, CHK1, and RAD51 would result in weakened repair of DNA DSBs induced by DNA damaging chemotherapeutic agents (e.g., cytarabine or DNR), thus enhancing apoptosis. At the same time, downregulation of BRCA1 and CHK1 by HDACIs would result in abrogation of cell cycle checkpoint activation (S and/or G2/M) induced by DNA damaging agents, thus forcing cells carrying DNA lesions to progress in the cell cycle and undergo apoptosis.