Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.
Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.
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DOI：
10.1038/srep24712
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发表时间：
2016-04-20
影响因子：
4.6
通讯作者：
Maeshima K
中科院分区：
文献类型：
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作者：
Imai R;Komeda S;Shimura M;Tamura S;Matsuyama S;Nishimura K;Rogge R;Matsunaga A;Hiratani I;Takata H;Uemura M;Iida Y;Yoshikawa Y;Hansen JC;Yamauchi K;Kanemaki MT;Maeshima K
染色质DNA必须被读出用于各种细胞功能，并为下一次细胞分裂复制。这些过程是许多抗癌药物的靶点。铂类药物，如顺铂，已被广泛用于癌症化疗。药物-DNA相互作用引起DNA交联和随后的细胞毒性。最近，据报道，唑桥双核铂（II）配合物，5-H-Y，表现出不同的抗癌谱从顺铂。在这里，我们使用跨学科的方法揭示了5-H-Y的细胞毒性机制与顺铂的细胞毒性机制不同。5-H-Y抑制DNA复制和RNA转录，将细胞阻滞在S/G2期，并对顺铂耐药癌细胞有效。此外，它引起的DNA交联比顺铂少得多，并诱导染色质折叠。5-H-Y将扩大其在治疗化疗不敏感癌症方面的临床应用。
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.