TY - JOUR
T1 - QS-ZYX-1-61 induces apoptosis through topoisomerase II in human non-small-cell lung cancer A549 cells
AU - Chen, Mei Chuan
AU - Pan, Shiow Lin
AU - Shi, Qian
AU - Xiao, Zhiyan
AU - Lee, Kuo Hsiung
AU - Li, Tsai Kun
AU - Teng, Che Ming
PY - 2012/1
Y1 - 2012/1
N2 - 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 VP-16 in suppressing the viability of A549 cells. Treatment of cells with QS-ZYX-1-61 led to a DNA damage response 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 IIα, and topo IIβ greatly protected against caspase-3 activation, poly-ADP-ribose polymerase cleavage, and cell growth inhibition, indicating that QS-ZYX-1-61 acts through these proteins. These results support our conclusion that QS-ZYX-1-61has potential as an anticancer agent because it causes accumulation of DNA cleavable complexes, with downstream consequences that include double-strand breaks and DNA damage response 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.
AB - 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 VP-16 in suppressing the viability of A549 cells. Treatment of cells with QS-ZYX-1-61 led to a DNA damage response 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 IIα, and topo IIβ greatly protected against caspase-3 activation, poly-ADP-ribose polymerase cleavage, and cell growth inhibition, indicating that QS-ZYX-1-61 acts through these proteins. These results support our conclusion that QS-ZYX-1-61has potential as an anticancer agent because it causes accumulation of DNA cleavable complexes, with downstream consequences that include double-strand breaks and DNA damage response 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.
UR - http://www.scopus.com/inward/record.url?scp=84855517944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855517944&partnerID=8YFLogxK
U2 - 10.1111/j.1349-7006.2011.02103.x
DO - 10.1111/j.1349-7006.2011.02103.x
M3 - Article
C2 - 21920000
AN - SCOPUS:84855517944
SN - 1347-9032
VL - 103
SP - 80
EP - 87
JO - Cancer Science
JF - Cancer Science
IS - 1
ER -