PT  - JOURNAL ARTICLE
AU  - Chao-Xin Hu
AU  - Zhi-Li Zuo
AU  - Bing Xiong
AU  - Jin-Gui Ma
AU  - Mei-Yu Geng
AU  - Li-Ping Lin
AU  - Hua-Liang Jiang
AU  - Jian Ding
TI  - Salvicine Functions as Novel Topoisomerase II Poison by Binding to ATP Pocket
AID  - 10.1124/mol.106.027714
DP  - 2006 Nov 01
TA  - Molecular Pharmacology
PG  - 1593--1601
VI  - 70
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/70/5/1593.short
4100  - http://molpharm.aspetjournals.org/content/70/5/1593.full
SO  - Mol Pharmacol2006 Nov 01; 70
AB  - Salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, is a nonintercalative topoisomerase II (topo II) poison. The compound possesses potent in vitro and in vivo antitumor activity with a broad spectrum of anti-multidrug resistance activity and is currently in phase II clinical trials. To elucidate the distinct antitumor properties of salvicine and obtain valuable structural information of salvicine-topo II interactions, we characterized the effects of salvicine on human topo IIα (htopo IIα), including possible binding sites and molecular interactions. The enzymatic assays disclosed that salvicine mainly inhibits the catalytic activity with weak DNA cleavage action, in contrast to the classic topo II poison etoposide (VP16). Molecular modeling studies predicted that salvicine binds to the ATP pocket in the ATPase domain and superimposes on the phosphate and ribose groups. In a surface plasmon resonance binding assay, salvicine exhibited higher affinity for the ATPase domain of htopo IIα than ATP and ADP. Competitive inhibition tests demonstrated that ATP competitively and dose-dependently blocked the interactions between salvicine and ATPase domain of htopo IIα. The data illustrate that salvicine shares a common binding site with ATP and functions as an ATP competitor. To our knowledge, this is the first report to identify an ATP-binding pocket as the structural binding motif for a nonintercalative eukaryotic topo II poison. These findings collectively support the potential value of an ATP competitor of htopo IIα in tumor chemotherapy. The American Society for Pharmacology and Experimental Therapeutics