title: Phenoxodiol (2H-1-benzopyran-7-0,1,3-(4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex.
abstract: Cancer therapeutic drugs that inhibit DNA topoisomerase (topo) II by stabilizing the cleavable complex are collectively known as topo II poisons. Phenoxodiol is a synthetic derivative of the plant isoflavone daidzein and is currently undergoing clinical testing as a cancer therapeutic drug. The development of this agent as an antitumor drug was based to a large extent on its low toxicity in normal tissues but potent topo II inhibitory effects in rapidly dividing tumor cells. To evaluate phenoxodiol as a potential inhibitor of topoisomerases, we used the relaxation and nicking assays that can identify topo I inhibitors, and the unknotting and DNA cleavage assays that can identify topo II inhibitors. Phenoxodiol inhibited the catalytic activity of topo II in a dose-dependent manner and it stabilized the topo II-mediated cleavable complex, demonstrating that this agent is a topo II poison. Phenoxodiol's topo II inhibitory effects were comparable to those of other antitumor agents such as VP-16 and were stronger than those of genistein. Phenoxodiol did not inhibit topo I catalytic activity nor did it stabilize the topo I-mediated cleavable complex. These results demonstrate that phenoxodiol is a topo II-specific poison and suggest that this novel agent may find applications in cancer chemotherapy.
authors.affiliation: Department of Surgical Oncology, College of Medicine, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Constantinou
authors.forename: Alan
authors.initials: A
authors.lastname: Husband
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones; D010636:Phenols / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D007529:Isoflavones; D010636:Phenols; D059005:Topoisomerase II Inhibitors; D004247:DNA; C471183:phenoxodiol