Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases andThe Johns Hopkins University-National Institutes of Health Graduate Partnership Program, National Institutes of Health, Bethesda, MD 20892; and.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9133-8. doi: 10.1073/pnas.1405739111. Epub 2014 Jun 9.
Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η- cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.
铂类药物是癌症化疗的主要药物。然而，肿瘤常常对铂类治疗表现出内在或获得性耐药，促使人们寻找新的化合物，这些化合物与当前的治疗方法没有交叉耐药性。菲咯嗪，顺二氨二氯菲咯啉铂(II)，是一种有效的单功能铂配合物，其活性谱与临床批准的铂类药物不同。菲咯嗪损伤对 RNA 聚合酶的抑制作用已被认为是其作用机制。本研究评估了菲咯嗪损伤抑制 DNA 复制的能力，这是传统铂类药物破坏的功能。菲咯嗪损伤能有效抑制 DNA 聚合酶 ν、ζ 和 κ 以及 Klenow 片段。与顺铂损伤产生的结果相反，所有这些聚合酶都能够在菲咯嗪损伤的对面插入一个碱基，但只有 Pol η，一种在跨损伤合成中有效的酶，能够完全绕过加合物，尽管效率很低。X 射线结构表征表明，Pol η 与在插入和+1 延伸步骤中特异性铂化的 DNA 复合物，菲咯嗪与 DNA 的相互作用并抑制 Pol η 的方式与顺铂-DNA 加合物不同。与顺铂和奥沙利铂不同，其效力受 Pol η 表达的影响，菲咯嗪对 Pol η+和 Pol η-细胞都具有高度毒性。鉴于 Pol η 的表达增加是细胞抵抗顺铂治疗的已知机制，因此菲咯嗪在治疗对顺铂敏感或容易产生耐药性的癌症方面可能具有价值。
