The mechanism of antiproliferative activity of the oxaliplatin pyrophosphate derivative involves its binding to nuclear DNA in cancer cells
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
37624480
DOI
10.1007/s00775-023-02017-x
PII: 10.1007/s00775-023-02017-x
Knihovny.cz E-zdroje
- Klíčová slova
- Anticancer, Cisplatin, DNA, Mechanism of action, Oxaliplatin, Phosphaplatin,
- MeSH
- cisplatina farmakologie MeSH
- difosfáty farmakologie MeSH
- DNA metabolismus MeSH
- nádory * MeSH
- organoplatinové sloučeniny farmakologie metabolismus MeSH
- oxaliplatin farmakologie MeSH
- platina farmakologie MeSH
- protinádorové látky * farmakologie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cisplatina MeSH
- difosfáty MeSH
- diphosphoric acid MeSH Prohlížeč
- DNA MeSH
- organoplatinové sloučeniny MeSH
- oxaliplatin MeSH
- platina MeSH
- protinádorové látky * MeSH
(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.
Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 61265 Brno Czech Republic
Department of Biophysics Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic
Department of Chemistry Università degli Studi di Bari Aldo Moro Via E Orabona 4 70126 Bari Italy
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