Open AccessInhibition of Topoisomerase II by a Novel Antitumor Cyclic Depsipeptide, BE‐22179
Author(s) -
Yoshinari Tomoko,
Okada Hiromasa,
Yamada Akihiro,
Uemura Daisuke,
Oka Hirofumi,
Suda Hiroyuki,
Okura Akira
Publication year - 1994
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1994.tb02394.x
Subject(s) - topoisomerase , dna , topoisomerase inhibitor , biochemistry , cytotoxicity , quinoxaline , biology , enzyme , dna synthesis , enzyme inhibitor , biological activity , depsipeptide , chemistry , microbiology and biotechnology , in vitro , organic chemistry
BE‐22179, a novel cyclic depsipeptide antibiotic having two 3‐hydroxyquinoline moieties, inhibited the DNA‐relaxing activity of L1210 topoisomerase II completely at 0.08 μM . This effect was far stronger than that of VP‐16. However, it did not show any marked effect on topoisomerase II‐mediated DNA cleavage. BE‐22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 μM , but showed DNA‐intercalating ability (DNA unwinding) at 30 μM . The structure of BE‐22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE‐22179, interfered with DNA relaxation by topoisomerase II, though the effect was not due to inhibition of the catalytic activity of topoisomerase II but to conformational change of DNA based on its intercalation into DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might rather be specific to BE‐22179. BE‐22179 prevented DNA synthesis as well as RNA synthesis in L1210 cells and inhibited the growth of the cells. However, it remains unclear to what extent the topoisomerase II inhibition was responsible for the cytotoxicity of BE‐22179.