(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC₅₀ values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.

Graphical abstract

中文翻译：

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奥沙利铂焦磷酸衍生物的抗增殖活性机制涉及其与癌细胞核 DNA 的结合

(1R,2R-二氨基环己烷)(二氢焦磷酸)铂(II)，也缩写为RRD2，属于一类称为磷铂的有效抗肿瘤铂细胞抑制剂。奇怪的是，几项已发表的研究表明磷铂和传统铂类抗肿瘤药物之间存在显着的机制差异。关于 RRD2 与 DNA 结合在其抗癌细胞增殖活性机制中的作用，已经发表了有争议的研究结果。这促使我们进行详细的研究，以确认或排除 RRD2 与 DNA 结合在其抗癌细胞增殖作用中的作用。在这里，我们证明RRD2在各种癌细胞系中表现出优异的抗增殖活性，IC ₅₀值在低微摩尔或亚微摩尔范围内。此外，这项研究的结果表明，RRD2 引起的 DNA 损伤有助于杀死用这种磷铂衍生物治疗的癌细胞。此外，我们的数据表明 RRD2 在癌细胞中积累，但程度低于顺铂。另一方面，顺铂和 RRD2 在癌细胞中积累后与核 DNA 的结合效率相似。我们的结果还表明，在RRD2在细胞内积累之前培养细胞的培养基中的RRD2保持完整。这一结果与RRD2仅在癌细胞环境中通过释放游离焦磷酸盐被激活从而使RRD2与核DNA结合的观点一致。

图形概要