A dual mechanism of action of the anticancer agent F 11782 on human topoisomerase II alpha.
F 11782 is a novel epipodophyllotoxin that targets eukaryotic topoisomerases and inhibits enzyme binding to DNA. While F 11782 has not been found to stabilize either topoisomerase I or topoisomerase II covalent complexes, drug treatment appears to result in DNA damage. F 11782 has also been shown to inhibit the DNA nucleotide excision repair (NER) pathway. Bisdioxopiperazine-resistant small cell lung cancer (SCLC) OC-NYH/Y165S and Chinese hamster ovary (CHO) CHO/159-1 cells having functional Y49F and Y165S mutations in the topoisomerase II alpha isoform were both resistant to F 11782. The catalytic activity of purified human Y50F and Y165S mutant topoisomerase II alpha (Y50F in the human protein corresponds to Y49F in the CHO protein) was likewise resistant to the inhibitory action of F 11782. F 11782 was also found to induce a non-covalent salt-stable complex of human topoisomerase II with DNA that was ATP-independent. F 11782 thus displays a dual mechanism of action on human topoisomerase II alpha, reducing its affinity for DNA while also stabilizing the protein bound in the form of a salt-stable complex. Our results suggest that topoisomerase II alpha is a target of F 11782 in vivo, and that F 11782 may act as a novel topoisomerase II poison.
Jensen
Lars H
LH
Department of Pathology, Laboratory Center, Rigshospitalet 5444, Frederik V's Vej 11, DK-2100 Copenhagen, Denmark. lhjensen@rh.dk
Renodon-Cornière
Axelle
A
Nitiss
Karin C
KC
Hill
Bridget T
BT
Nitiss
John L
JL
Jensen
Peter B
PB
Sehested
Maxwell
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II; C405744:tafluposide