Open AccessQS‐ZYX‐1‐61 induces apoptosis through topoisomerase II in human non‐small‐cell lung cancer A549 cells
Author(s) -
Chen MeiChuan,
Pan ShiowLin,
Shi Qian,
Xiao Zhiyan,
Lee KuoHsiung,
Li TsaiKun,
Teng CheMing
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.02103.x
Subject(s) - topoisomerase , apoptosis , dna damage , poly adp ribose polymerase , dna , a549 cell , programmed cell death , biology , microbiology and biotechnology , cleavage (geology) , cell , viability assay , polymerase , chemistry , biochemistry , paleontology , fracture (geology)
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‐1‐61 has 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. ( Cancer Sci 2012; 103: 80–87)