title: QS-ZYX-1-61 induces apoptosis through topoisomerase II in human non-small-cell lung cancer A549 cells.
abstract: 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.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Chen
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C570303:4-((4'-benzylpiperdin-4-yl)amino)-4'-O-demethylepipodophyllotoxin; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D010880:Piperidines; D034741:RNA, Small Interfering; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin