Poly (ADP-ribose) polymerase inhibition synergizes with the NF-kB inhibitor DHMEQ to kill hepatocellular carcinoma cells.

Dehydroxymethylepoxyquinomicin (DHMEQ), a new inhibitor of NF-kB, induces oxidative stress and DNA damage. Poly (ADP-Ribose) Polymerase (PARP) enzymes play a key role in the cellular machinery responsible for DNA repair. The effects of DHMEQ in combination with Olaparib (PARP inhibitor) were studied on hepatocellular carcinoma cells (HCC). The DHMEQ-Olaparib combination synergistically inhibited cell viability, cell proliferation and colony formation of Hep3B, but had additive effects on Huh7 cells. The synergistic effects of the combination correlated with increased caspase 3/7 activity and PARP cleavage. ROS production was increased after DHMEQ-Olaparib treatment of Hep3B, which caused DNA damage by an accumulation of ?H2AX and reduced cell viability. The combination reduced Rad51 nuclear foci in Hep3B cells (not Huh7 cells), and silencing of Rad51 enhanced sensitivity of Huh7 cells to the DHMEQ-Olaparib combination. Treatment of Hep3B cells with DHMEQ-Olaparib increased ROS-induced AKT phosphorylation which decreased the formation of Rad51 nuclear foci. In conclusion the DHMEQ-Olaparib combination induced ROS production which killed HCC cells via DNA damage that could not be repaired by Rad51.