Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.
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.
Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.|Department of Genetics, School of Life Science, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.
Ryosuke
R
Imai
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670.
Seiji
S
Komeda
CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.|Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan.|RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
Mari
M
Shimura
Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.|CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Sachiko
S
Tamura
CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.|RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.|Department of Precision Science &Technology, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka Suita, Osaka, Japan 565-0871.
Satoshi
S
Matsuyama
Center for Frontier Research, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
Kohei
K
Nishimura
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
Ryan
R
Rogge
CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.|Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan.|RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
Akihiro
A
Matsunaga
Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.|Department of Genetics, School of Life Science, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.|Laboratory for Developmental Epigenetics, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Ichiro
I
Hiratani
Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.|Frontier Research Base for Global Young Researchers, Graduate School of Engineering Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Hideaki
H
Takata
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670.
Masako
M
Uemura
Inorganic Analysis Laboratories, Toray Research Center, Inc., 3-3-7, Sonoyama, Otsu, Shiga 520-8567, Japan.
Yutaka
Y
Iida
Research Organization of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
Yuko
Y
Yoshikawa
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
Jeffrey C
JC
Hansen
CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.|RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.|Department of Precision Science &Technology, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka Suita, Osaka, Japan 565-0871.
Kazuto
K
Yamauchi
Department of Genetics, School of Life Science, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.|Center for Frontier Research, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.|PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Masato T
MT
Kanemaki
Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.|Department of Genetics, School of Life Science, Sokendai (Graduate University for Advanced Studies), Mishima, Shizuoka 411-8540, Japan.|CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.|RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan.
Kazuhiro
K
Maeshima
D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D006657:Histones; D009944:Organoplatinum Compounds; D013777:Tetrazoles; C045574:1H-tetrazole; D002945:Cisplatin