While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib.
The results showed that C10 regulated the expression of Bax, c-Myc, Bcl-2, P38/AMPK and ERK 1/2, activated the expression of Caspase-3, -8, and PARP at the protein level in the apoptosis pathway of the two leukemia cell types, and inhibited the expression of erythroleukemia carcinogene Fli-1 in the human erythroleukemia cell line HEL.
Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells.
Consistent with increased DNA damage accumulation induced by RUNX1-ETO, PARP inhibition has been shown to be an effective synthetic-lethal therapeutic approach against RUNX1-ETO expressing leukemias.