The role of cisplatin and NAMI-A plasma-protein interactions in relation to combination therapy

Abstract

Abstract. The aim of the study is to evaluate the differences of protein binding of NAMI-A, a new ruthenium drug endowed with selective antimetastatic properties, and of cisplatin and to ascertain the possibility to use two drugs based on heavy metals in combination to treat solid tumour metastases. For this purpose, we have developed a technique that allows the proteins, to which metal drugs bind, to be identified from real protein mixtures. Following incubation with the drugs, the bands containing platinum and/or ruthenium are separated by native PAGE, SDS-PAGE and 2D gel electrophoresis, and identified using laser ablation inductively coupled plasma mass spectrometry. Both drugs interact with essentially the same proteins which, characterised by proteomics, are human serum albumin precursor, macroglobulin ·2 and human serotransferrin precursor. The interactions of NAMI-A are largely reversible whereas cisplatin forms stronger interactions that are less reversible. These data correlate well with the MCa mammary carcinoma model on which full doses of NAMI-A combined with cisplatin show additive effects as compared to each treatment taken alone, independently of whether NAMI-A precedes or follows cisplatin. Furthermore, the implication from this study is that the significantly lower toxicity of NAMI-A, compared to cisplatin, could be a consequence of differences in the mode of binding to plasma proteins, involving weaker interactions compared to cisplatin.

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

“…Indeed, it is very likely that the effective targets for the metallodrug investigated are to be searched for among the proteins with which the metal is tightly associated. A few notable examples of this kind of strategy are available in the recent literature [25][26][27][28]. Nowadays, metallomic studies may take particular advantage of the use of very sensitive hyphenated methods as extensively documented by Becker et al [29] and by other research groups in a few recent papers and reviews.…”

Novel microwave synthesis of half‐sandwich [(η6‐C6H6)Ru] complexes and an evaluation of the biological activity and biochemical reactivity

“…In fact, it is believed that proteins associated with metastatic cells might be the true molecular targets. [9,10] KP1016 is also believed to be following a mechanism involving transferrin. We have reported [11,12] that some half-sandwich ruthenium complexes, [(Z 6 -p-cymene)Ru(thiosemicarbazone)Cl] + , can inhibit the activity of the topoisomerase II enzyme.…”

Characterisation of Cisplatin Binding Sites in Human Serum Proteins Using Hyphenated Multidimensional Liquid Chromatography and ESI Tandem Mass Spectrometry

“…[5] A recent LA-ICP-MS (laser ablation inductively coupled plasma mass spectrometry) study of Pt-binding plasma proteins that had been separated by SDS-PAGE has confirmed human serum albumin (HSA), serotransferrin (Trfe) and a-2-macroglobulin (A2mg) as major serum targets for cisplatin following a 12 h incubation period. [8] ESI-Q-TOF mass spectrometry has been employed to detect an intact HSA adduct that contained approximately four cisplatin fragments. [9] A 1:1 stoichiometry was observed in the case of Trfe.…”