A comparison study on RNase A oligomerization induced by cisplatin, carboplatin and oxaliplatin

Picone, Delia; Donnarumma, Federica; Ferraro, Giarita; Gotte, Giovanni; Fagagnini, Andrea; Butera, Giovanna; Donadelli, Massimo; Merlino, Antonello

doi:10.1016/j.jinorgbio.2017.05.005

Cited by 13 publications

(8 citation statements)

References 46 publications

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“…The Pt II -coordinated Sub P dimer appeared at significantly lower abundance, and no higher oligomers were observed. Similar findings were reported by Merlino et al [51], who investigated the formation of cisplatin interprotein crosslinks and platinated oligomers of RNase A.…”

Section: Resultssupporting

confidence: 89%

Top-down mass spectrometry reveals multiple interactions of an acetylsalicylic acid bearing Zeise’s salt derivative with peptides

Cziferszky

Gust

2020

J Biol Inorg Chem

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Synergistic effects and promising anticancer activities encourage the combination of non-steroidal anti-inflammatory drugs with metallodrugs. Here, we discuss the interactions of an organometallic complex consisting of an acetylsalicylic acid (ASA) moiety attached to a Pt II center via an alkenol linker in a Zeise's salt-type coordination (ASA-buten-PtCl 3) with model peptides angiotensin 1 (AT), substance P (Sub P), and ubiquitin (UQ). Top-down mass spectrometry experiments show that the amino acid involved in the initial binding to the metal complex controls the coordination sphere of Pt II in the adducts. The strong trans labilizing effect of the coordinating sulfur atom in Met causes fast release of the organic moiety and leads to the formation of dimers and oligomers in the case of Sub P. In contrast, interactions with nitrogen donors in AT result in stable adducts containing the intact ASA-buten-Pt II complex. UQ forms two sets of Pt II adducts, only one of them retains the ASA moiety, which is presumably the result of an unexpected binding geometry. Importantly, UQ is additionally acetylated at various Ser and Lys residues by the ASA-buten-PtCl 3 complex. Control experiments with ASA are negative. This is the first example of concomitant platination and acetylation of a peptide with an ASA metal complex.

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Section: Resultssupporting

confidence: 89%

Top-down mass spectrometry reveals multiple interactions of an acetylsalicylic acid bearing Zeise’s salt derivative with peptides

Cziferszky

Gust

2020

J Biol Inorg Chem

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“…The inspection of the electron density maps reveals the presence of Pt complex fragments close to His105 in both molecules of the a. u. (Figure 5), as observed in the structure of RNase A in complex with 1Pt-Im [18] and in the case of other RNase A–Pt-based drug adducts [42,43]. The interpretation of the electron density map at the two different Pt-binding sites is rather difficult.…”

Section: Resultsmentioning

confidence: 98%

Reaction with Proteins of a Five-Coordinate Platinum(II) Compound

Ferraro

Marzo

Cucciolito

et al. 2019

IJMS

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Stable five-coordinate Pt(II) complexes have been highlighted as a promising and original platform for the development of new cytotoxic drugs. Their interaction with proteins has been scarcely studied. Here, the reactivity of the five-coordinate Pt(II) compound [Pt(I)(Me) (dmphen)(olefin)] (Me = methyl, dmphen = 2,9-dimethyl-1,10-phenanthroline, olefin = dimethylfumarate) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) has been investigated by X-ray crystallography and electrospray ionization mass spectrometry. The X-ray structures of the adducts of RNase A and HEWL with [Pt(I)(Me)(dmphen)(olefin)] are not of very high quality, but overall data indicate that, upon reaction with RNase A, the compound coordinates the side chain of His105 upon releasing the iodide ligand, but retains the pentacoordination. On the contrary, upon reaction with HEWL, the trigonal bi-pyramidal Pt geometry is lost, the iodide and the olefin ligands are released, and the metal center coordinates the side chain of His15 probably adopting a nearly square-planar geometry. This work underlines the importance of the combined use of crystallographic and mass spectrometry techniques to characterize, in detail, the protein–metallodrug recognition process. Our findings also suggest that five-coordinate Pt(II) complexes can act either retaining their uncommon structure or functioning as prodrugs, i.e., releasing square-planar platinum complexes as bioactive species.

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Section: Rnase Oligomerization: a Strategy To Obtain Stable And More mentioning

confidence: 99%

“…More recently, oligomers have been produced also upon mixing at 37°C RNase A with metallic derivatives commonly used as chemotherapeutic agents, such as cisplatin, or also carbo- or oxaliplatin (195, 196). The yield of RNase A-cisplatin oligomers remarkably increases with the cisplatin/protein ratio (195), while with the other Pt adduct yields are definitely lower (196). Unfortunately, these adducts are endowed with scarce ribonucleolytic activity and lack cytotoxicity principally because the catalytic H119 residue is directly involved in the linking with the metallic moiety (195, 196).…”

Section: Rnase Oligomerization: a Strategy To Obtain Stable And More mentioning

confidence: 99%

“…The yield of RNase A-cisplatin oligomers remarkably increases with the cisplatin/protein ratio (195), while with the other Pt adduct yields are definitely lower (196). Unfortunately, these adducts are endowed with scarce ribonucleolytic activity and lack cytotoxicity principally because the catalytic H119 residue is directly involved in the linking with the metallic moiety (195, 196). Hence, this result helps to explain why cisplatin and/or similar adducts display a reduced efficacy and undesired side-effects in therapy: in fact, this is because they very probably affect proteins, such as here RNase A, or in vivo serum albumin as well, at a higher extent than the desired DNA target.…”

Section: Rnase Oligomerization: a Strategy To Obtain Stable And More mentioning

confidence: 99%

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Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

Gotte

Menegazzi

2019

Front. Immunol.

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Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections. Instead, if they enter the cell, RNases can digest intracellular RNAs, becoming cytotoxic and having advantageous effects against malignant cells. Their biological activities have been investigated either in vitro, toward a number of different cancer cell lines, or in some cases in vivo to test their potential therapeutic use. However, immunogenicity or other undesired effects have sometimes been associated with their action. Nevertheless, the use of RNases in therapy remains an appealing strategy against some still incurable tumors, such as mesothelioma, melanoma, or pancreatic cancer. The RNase inhibitor (RI) present inside almost all cells is the most efficacious sentry to counteract the ribonucleolytic action against intracellular RNAs because it forms a tight, irreversible and enzymatically inactive complex with many monomeric RNases. Therefore, dimerization or multimerization could represent a useful strategy for RNases to exert a remarkable cytotoxic activity by evading the interaction with RI by steric hindrance. Indeed, the majority of the mentioned RNases can hetero-dimerize with antibody derivatives, or even homo-dimerize or multimerize, spontaneously or artificially. This can occur through weak interactions or upon introducing covalent bonds. Immuno-RNases, in particular, are fusion proteins representing promising drugs by combining high target specificity with easy delivery in tumors. The results concerning the biological features of many RNases reported in the literature are described and discussed in this review. Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects.

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A comparison study on RNase A oligomerization induced by cisplatin, carboplatin and oxaliplatin

Cited by 13 publications

References 46 publications

Top-down mass spectrometry reveals multiple interactions of an acetylsalicylic acid bearing Zeise’s salt derivative with peptides

Top-down mass spectrometry reveals multiple interactions of an acetylsalicylic acid bearing Zeise’s salt derivative with peptides

Reaction with Proteins of a Five-Coordinate Platinum(II) Compound

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs

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