Analysis of inhibition of topoisomerase II alpha and cancer cell proliferation by ingenolEZ

作者：Yoshida Chisato; Hishiyama Kazsuyoshi; Miyazaki Khosuke; Watanabe Manami; Kanbe Masahiro; Yamada Yuta; Matsuzaki Keiithi; Miyashita Kiichi; Kitanaka Susumu; Miyata Shohei^*

来源：Cancer Science, 2010, 101(2): 374-378.

DOI：10.1111/j.1349-7006.2009.01408.x

We previously reported that many ingenol compounds derived from Euphorbia kansui exhibit topoisomerase inhibitory activity and/or inhibitory activity of cell proliferation. The inhibitory effects of 20-O-(2'E,4'Z-decadienoyl) ingenol and 3-O-(2'E,4'Z-decadienoyl)-ingenol among these compounds on topoisomerase II activity and on the cell proliferative activity and arrest phase of the cell cycle were studied using a mouse breast cancer (MMT) cell line. Although 20-O-ingenolEZ exerted inhibitory effects on both topoisomerase II activity and cell proliferative activity, 3-O-ingenolEZ exerted inhibitory activity on neither. The 20-O-ingenolEZ-induced cell arrest of MMT-cell proliferation led to a cell cycle arrest in the G2/M phase. Topoisomerase II inhibition can be divided into the poison and catalytic inhibitor types. A checkpoint mechanism is activated when cells are treated with these topoisomerase II inhibitors. Poison-type inhibition occurs via induction of the DNA damage checkpoint and the catalytic-type inhibition occurs via induction of the DNA-decatenation checkpoint, suggestive of distinct checkpoint reactions. 20-O-ingenolEZ inhibited topoisomerase II alpha activity through inhibition of ATPase, and induced DNA-decatenation checkpoint without signaling for phosphorylation of H2AX. (Cancer Sci 2010; 101: 374-378).

• 出版日期2010-2