A novel antitumor platinum complex

Biological Macromolecules Laboratory / Maeshima Group

Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex

Ryosuke Imai, Seiji Komeda, Mari Shimura, Sachiko Tamura, Satoshi Matsuyama, Kohei Nishimura, Ryan Rogge, Akihiro Matsunaga, Ichiro Hiratani, Hideaki Takata, Masako Uemura, Yutaka Iida, Yuko Yoshikawa, Jeffrey C. Hansen, Kazuto Yamauchi, Masato T. Kanemaki, and Kazuhiro Maeshima

Scientific Reports 6, Article number: 24712 (2016) DOI:10.1038/srep24712

Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug–DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum (II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective to cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers.

Figure1

5-H-Y inhibits DNA replication and arrests the treated cells in S/G2 phase. 5-H-Y binds tightly to chromatin DNA and induces chromatin folding in vitro and in vivo.


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