B1, a novel topoisomerase II inhibitor, induces apoptosis and cell cycle G1 arrest in lung adenocarcinoma A549 cells |
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Authors: | Cheng Meng-Hsuan Yang Yu-Chiao Wong Yun-Hong Chen Tsuei-Ru Lee Chia-Yu Yang Chun-Chien Chen Shih-Hua Yang I-Ning Yang Ya-Shiu Huang Hsu-Shan Yang Chun-Yuh Huang Ming-Shyan Chiu Hui-Fen |
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Affiliation: | Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ho Memorial Hospital, Taipei, Taiwan, ROC. |
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Abstract: | In our previous studies, we demonstrated that 2,6-bis-(2-chloroacetamido) anthraquinone (B1) showed a highly significant cytotoxic effect. However, its influence in the cell cycle and apoptotic induction effects has not been investigated yet. Here we report the antiproliferative effect of B1, for which IC50 values were 0.57 μmol/l for lung cancer A549 cells, 0.63 μmol/l for colon cancer HT-29 cells, and 0.53 μmol/l for breast cancer MCF-7 cells. DNA topoisomerase II (Topo II), an essential enzyme in DNA synthesis and meiotic division, is highly expressed in cancer cells. Some currently used clinical anticancer drugs (doxorubicin and mitoxantrone) targeting Topo II are very effective antineoplastic agents. B1, sharing the basic structure of known Topo II inhibitors, demonstrated a significant inhibitory effect on Topo II bioactivity. In A549 cells, B1 increased apoptotic cell population with induction of Fas, Bax, and cleaved poly(ADP-ribose) polymerase and by reduction of Bcl-2 expression. Moreover, cell cycle analysis indicated that B1 induced G1 phase arrest through modulation of G1 cell cycle regulatory proteins, such as the downregulation of cyclin D1 and upregulation of Cip/p21, Kip1/p27, and p53. Thus, our study suggests that B1, with the ability to inhibit Topo II activity and cause cell cycle G1 arrest and apoptosis, has potential as a novel anticancer agent. |
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