Abstract
The ruthenium-based complex [Ru(η6-p-phenylethacrynate)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 (BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A > G > T > C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA.
Highlights
Since the introduction of cisplatin [cis-dichlorodiammineplatinum(II)], and its analog carboplatin [cis-diammine-(1,1-cyclobutanedicarboxylato) platinum(II)] into clinical practice [1,2,3,4] there has been much interest in the development of anticancer drugs
We investigate the interactions of ethaRAPTA with the specified DNA sequence of the human breast cancer suppressor gene 1 (BRCA1) gene in cells and a cell-free system
The electrophoretic mobility of ethaRAPTA-treated BRCA1 fragment was reduced as the concentration of ethaRAPTA increased (Figure 2)
Summary
Since the introduction of cisplatin [cis-dichlorodiammineplatinum(II)], and its analog carboplatin [cis-diammine-(1,1-cyclobutanedicarboxylato) platinum(II)] into clinical practice [1,2,3,4] there has been much interest in the development of anticancer drugs. RAPTA compounds contain a ruthenium(II)-arene unit with a PTA ligand [14] These complexes have been shown to interact with DNA in a pH-dependent manner [15,16] and offer cancer cell specific targeting. With the validation of ethacraplatin to overcome glutathione S-transferase (GST)-mediated drug resistance, a new RAPTA complex with EA tethered to the arene ring [(ethacrynic- 6-benzylamide)RuCl2(pta) or ethaRAPTA] (Figure 1), was developed, and investigated for GST-inhibitory activity and its effect on the proliferation of cancer cells. BRCA1 protein, has been shown to play an important role in genomic integrity maintenance such as DNA repair, cell-cycle checkpoint control, transcriptional regulation and protein ubiquitination [20,21,22] Approaching such a gene as a potentially molecular target for the antitumor ruthenium(II)-arene (RAPTA) compounds might be of interest in cancer therapy. We investigate the interactions of ethaRAPTA with the specified DNA sequence of the human BRCA1 gene in cells and a cell-free system
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