Model for NU7026 mechanism of action. Schematic representing our model for the mechanism by which NU7026 potentiates topo II poison cytotoxicity. The topo II-DNA complex is an intermediate step in the catalytic cycle during which the enzyme passes one DNA duplex through another (via a covalent protein-bridged DNA break) and then religates the cleaved DNA. Treatment with detergent can disrupt or cleave these complexes, hence the term “cleavable complexes.” However, treatment of cells with topo II poisons (eg, etoposide) results in stabilization of the normally transient cleavable complex. After stabilization by drugs, complexes may be processed into DNA DSB, stimulating activation of DNA repair enzymes. Recruitment of DNA-PK to DSB facilitates nonhomologous end joining and therefore repair of DNA. However, in the presence of NU7026, DNA-PK activity is inhibited, NHEJ is impeded, and thus persistence of DNA damage leads to cell death.