"Platinum on the road": Interactions of antitumoral cisplatin with proteins

Abstract

When the antitumor activity of cisplatin was discovered, no one would have thought of the existence of specific proteins able to transport Pt across the cell membrane or to specifically recognize DNA modified by this drug. However, such proteins do exist and, furthermore, are specific for the Pt substrate considered. It follows that proteins are deeply involved in managing the biological activity of cisplatin. It is expected that, after the first 20 years in which most of the efforts were devoted to understanding its mode of interaction with DNA and consequent structural and functional alterations, the role of proteins will be more deeply scavenged. How cisplatin can survive the attack of the many platinophiles present in the extracellular and intracellular media is the issue addressed in this article. Significantly, differences are observed between cisplatin, carboplatin, and oxaliplatin.

Interactions of carboplatin and oxaliplatin with proteins: Insights from X-ray structures and mass spectrometry studies of their ribonuclease A adducts

“…1) have been implicated in extensive formation of Pt-protein adducts. Though the involvement of these adducts in the mode of action and toxicity of Pt drugs is still unclear, more and more attention is being placed upon protein-Pt drugs interactions in relation to their overall pharmacological and toxicological impact [8][9][10][11]. Yet, the structural information concerning the interactions of platinum drugs with proteins and the characterization of the resulting adducts is quite limited [8][9][10][11].…”

“…Though the involvement of these adducts in the mode of action and toxicity of Pt drugs is still unclear, more and more attention is being placed upon protein-Pt drugs interactions in relation to their overall pharmacological and toxicological impact [8][9][10][11]. Yet, the structural information concerning the interactions of platinum drugs with proteins and the characterization of the resulting adducts is quite limited [8][9][10][11]. In particular, while the interaction between cisplatin and proteins is underscored by a number of biochemical, biophysical and structural studies [12][13][14][15][16][17][18][19][20], the formation of oxaliplatin and carboplatinprotein adducts is far less explored and understood [21][22][23][24].…”

The reaction of a platinated methionine motif of CTR1 with cysteine and histidine is dependent upon the type of precursor platinum complex

“…The ESI-MS signal corresponds to [Pt(DACH)(Mets7)] 2+ . This result indicates that Mets7 substitutes the oxalate ligand of oxaliplatin, while the bidentate 1,2-diaminocyclohexane (DACH) ligand remains coordinated to platinum [24]. Most probably different methionine residues of Mets7 are involved in platinum coordination which explains the observation of multiple products in the HPLC profile.…”

Covalent and non-covalent binding of metal complexes to RNA

“…Even if cellular DNA is considered the main therapeutical active target for cisplatin, the latter could also interact [48] using PDB ID 1RNA [49] and 1BNA [50] respectively. with other biomolecules, like RNA [39] and proteins [67,68]. Studying the interaction of cisplatin with biomolecules other than DNA is important to obtain a clearer picture of its complex biological activity [39,67,68].…”

“…with other biomolecules, like RNA [39] and proteins [67,68]. Studying the interaction of cisplatin with biomolecules other than DNA is important to obtain a clearer picture of its complex biological activity [39,67,68]. Moreover, it is worth noting that intense research is being currently dedicated to the identification of new cellular targets for metallodrugs in general [69].…”