Agents that cause DNA damage have been widely used as anticancer drugs because DNA lesions can initiate DNA checkpoints that induce cell death. The results presented here indicate that QS-ZYX-1-61, a derivative of VP-16, was significantly more potent than etoposide (VP-16) in suppressing the viability of A549 cells. Treatment of cells with QS-ZYX-1-61 led to a DNA damage response (DDR) and a dramatic increase of apoptosis. Our results also suggest that QS-ZYX-1-61 may be a topoisomerase (topo) II targeting agent as evidenced by relaxation assay and induction of reversible cleavable complexes. Moreover, blocking of p53, topo IIalpha, and topo IIbeta greatly protected against caspase-3 activation, PARP cleavage, and cell growth inhibition, indicating that QS-ZYX-1-61 acts through these proteins. These results support our conclusion that QS-ZYX-1-61 has potential as an anti-cancer agent because it causes accumulation of DNA cleavable complexes, with downstream consequences that include double-strand breaks (DSBs) and DDR signaling for apoptosis. Taken together, our results indicate that QS-ZYX-1-61 is a novel DNA damaging agent and displays an outstanding activity that could be worthy of further investigation.
