TY - JOUR
T1 - Topoisomerase II-mediated DNA cleavage activity and irreversibility of cleavable complex formation induced by DNA intercalator with alkylating capability
AU - Kong, Xiang Bin
AU - Rubin, Lisa
AU - Chen, Luan Ing
AU - Ciszewska, Grazyna
AU - Watanabe, Kyoich A.
AU - Tong, William P.
AU - Sirotnak, Francis M.
AU - Chou, Ting Chao
PY - 1992/2
Y1 - 1992/2
N2 - A group of chrysophanol and emodin derivatives with DNA-intercalating capability and with or without alkylating potential have been synthesized and shown to have antitumor activity in vitro. The topoisomerase II (Topo II)-mediated DNA cleavage activities induced by representative compounds 3-(2-chloroethy-lamino)methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31690), 3-bis[(2-chloroethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31662), and 3-(2-hydroxyethylamino)methy-1,8-dihydroxy-9,10-anthraquinone (SK-31694), and their cytotoxicities, have been investigated. All three compounds inhibited the kinetoplast DNA decatenation catalyzed by DNA Topo II. These compounds inhibited leukemia cell growth and stimulated, in a dose-dependent manner from 0.5 to 60 μM, the formation of Topo II-DNA cleavable complexes, when 3′-32P-labeled DNA was used. The mapping of Topo II-mediated DNA cleavage sites using HindIII-digested 3′-32P-labeled DNA showed that, at 10 μM, these compounds induced protein-linked DNA breaks that correlated with cytotoxicity, with respect to their maximal efficacy or the reciprocal concentration for the half-maximal effect. The reversibility study showed that the amounts of protein-linked DNA cleavage induced by 4′-(9-acridinylamino)methanesulfon-m-anisidide and VP-16 as well as SK-31694, which lacks alkylating potential, were markedly decreased during 30-sec exposure to 65° or 0.5 M NaCl. In contrast, protein-linked DNA cleavages induced by SK-31662, which has two alkylating functionalities, and by SK-31690, which has one alkylating functionality in its structure, cannot be reversed during the 15-min exposure to 65° or 0.5 M NaCl. These data suggest that Topo II is a major cellular target for cytotoxicity of these compounds. Furthermore, DNA intercalators with alkylating potential interact with Topo II-DNA cleavable complexes in an irreversible manner, with enhanced toxicity.
AB - A group of chrysophanol and emodin derivatives with DNA-intercalating capability and with or without alkylating potential have been synthesized and shown to have antitumor activity in vitro. The topoisomerase II (Topo II)-mediated DNA cleavage activities induced by representative compounds 3-(2-chloroethy-lamino)methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31690), 3-bis[(2-chloroethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone (SK-31662), and 3-(2-hydroxyethylamino)methy-1,8-dihydroxy-9,10-anthraquinone (SK-31694), and their cytotoxicities, have been investigated. All three compounds inhibited the kinetoplast DNA decatenation catalyzed by DNA Topo II. These compounds inhibited leukemia cell growth and stimulated, in a dose-dependent manner from 0.5 to 60 μM, the formation of Topo II-DNA cleavable complexes, when 3′-32P-labeled DNA was used. The mapping of Topo II-mediated DNA cleavage sites using HindIII-digested 3′-32P-labeled DNA showed that, at 10 μM, these compounds induced protein-linked DNA breaks that correlated with cytotoxicity, with respect to their maximal efficacy or the reciprocal concentration for the half-maximal effect. The reversibility study showed that the amounts of protein-linked DNA cleavage induced by 4′-(9-acridinylamino)methanesulfon-m-anisidide and VP-16 as well as SK-31694, which lacks alkylating potential, were markedly decreased during 30-sec exposure to 65° or 0.5 M NaCl. In contrast, protein-linked DNA cleavages induced by SK-31662, which has two alkylating functionalities, and by SK-31690, which has one alkylating functionality in its structure, cannot be reversed during the 15-min exposure to 65° or 0.5 M NaCl. These data suggest that Topo II is a major cellular target for cytotoxicity of these compounds. Furthermore, DNA intercalators with alkylating potential interact with Topo II-DNA cleavable complexes in an irreversible manner, with enhanced toxicity.
UR - http://www.scopus.com/inward/record.url?scp=0026505809&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026505809&partnerID=8YFLogxK
M3 - Article
C2 - 1311406
AN - SCOPUS:0026505809
SN - 0026-895X
VL - 41
SP - 237
EP - 244
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -