Pt-based drugs: the spotlight will be on proteins

Abstract

Platinum-complexes represent some of the most successful groups of clinically used anticancer drugs. Their mechanism of action relies on the formation of stable DNA adducts occurring at the nitrogen in position 7 of guanine (N7) and involving one or two spatially close residues. The formation of stable DNA adducts is recognized as a DNA damaging event and, ultimately, drives cells to death. Nevertheless, nucleobases are not the only reliable targets of these drugs and other biomolecules can be involved. Among them large interest has been devoted to proteins since they contain several potential reactive sites for platinum (His, Met, and Cys) and, in particular, because the reaction of the metal with sulfur containing groups is a kinetically favored process. As a result, the occurrence of protein adducts and DNA-protein cross-links must be further taken into account in order to fully define cisplatin mechanism of action. Herein, we will summarize the most recent experimental evidence collected so far on protein-cisplatin adduct formation to better dissect its correlation with the drug pharmacological profile. Indeed, in addition to modulation of drug bioavailability and toxicity, the potential role of proteins as reaction intermediates or reservoir systems in platinum drugs can be envisaged. Additionally, the effects of Pt-coordinating groups on the chemical reactivity of the metal complexes will be reviewed. From all these outcomes a general model for Pt-based drugs mechanism of action can be drawn which is more articulate than the one currently supported. It claims proteins as reactive intermediates for DNA platination and it defines them as relevant to fully describe the clinical potential of this class of anticancer drugs.

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].…”

Oxaliplatin vs. cisplatin: competition experiments on their binding to lysozyme

“…6 In par-ticular, the toxicity profile of oxaliplatin greatly differs from that of cisplatin by its moderate nephrotoxicity and from that of carboplatin by its limited hematological toxicity. [10][11][12][13] During the last 15 years, protein platination by these three Pt-based drugs has been investigated by various techniques. [7][8][9] To better understand the pharmacological profiles of cisplatin, carboplatin and oxaliplatin it is imperative to study the mechanism by which these Pt drugs interact with proteins.…”

cis-Pt I2(NH3)2: a reappraisal

“…[4][5][6] A quite wide consensus now exists concerning the likely mode of action of anticancer Pt drugs that mainly relies on direct DNA damage, impairment of fundamental DNA functions and consequent triggering of apoptosis; 1,2 yet, several issues and details remain unexplored and/or unanswered, so that other mechanistic hypotheses -even DNA unrelatedhave been advanced. 7,8 The great clinical success of cisplatin has inspired an intense search for platinum analogues with hopefully improved biological and pharmacological properties; [9][10][11][12][13] however, the outcomes of these research activities turned out to be quite modest and disappointing, both in terms of identification of new clinically effective Pt agents and discovery of innovative modes of action.…”