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

• Published in: Scientific reports Vol. 6; no. 1; p. 24712
• Main Authors: Imai, Ryosuke, Komeda, Seiji, Shimura, Mari, Tamura, Sachiko, Matsuyama, Satoshi, Nishimura, Kohei, Rogge, Ryan, Matsunaga, Akihiro, Hiratani, Ichiro, Takata, Hideaki, Uemura, Masako, Iida, Yutaka, Yoshikawa, Yuko, Hansen, Jeffrey C, Yamauchi, Kazuto, Kanemaki, Masato T, Maeshima, Kazuhiro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.04.2016
• Subjects: Antineoplastic Agents - pharmacology; Antitumor agents; Cancer; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Chromatin; Chromatin Assembly and Disassembly - drug effects; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Repair; DNA Replication - drug effects; G2 phase; Histones - metabolism; Humans; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Platinum; Replication; Ribonucleic acid; RNA; Tetrazoles - chemistry; Tetrazoles - pharmacology; Therapeutic applications; Transcription; Transcription, Genetic - drug effects
• ISSN: 2045-2322; 2045-2322
• 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 against 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.