Enzymatic Processing of Platinated RNAs

Chapman, Erich G.; DeRose, Victoria J.

doi:10.1021/ja908419j

Cited by 34 publications

(43 citation statements)

References 65 publications

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“…addition, cisplatin causes atypical cross-links in structurally complex RNAs, thereby preventing reverse transcription, indicating that the RNA binding may interfere with communicating sequence information (18,19).…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics

Hato

Khong

Vries

et al. 2014

Clinical Cancer Research

388

286

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The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs.

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Section: Introductionmentioning

confidence: 99%

Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics

Hato

Khong

Vries

et al. 2014

Clinical Cancer Research

388

286

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“…A preference for interaction with the guanine base is observed for both compounds, in agreement with previous studies by us and others. 27,33À36 Depending on the more extended sequence context, different binding preferences are observed for the two studied metal complexes, however.…”

mentioning

confidence: 99%

Platinum Interference with siRNA Non-seed Regions Fine-Tunes Silencing Capacity

2011

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Knowledge concerning the molecular mechanisms governing the influence of non-coding RNAs on protein production has emerged rapidly during the past decade. Today, two main research areas can be identified, one oriented toward the use of artificially introduced siRNAs for manipulation of gene expression, and the other one focused on the function of endogenous miRNAs. In both cases, the active molecule consists of a ∼20-nucleotide-long RNA duplex. In the siRNA case, improved systemic stability is of central interest for its further development toward clinical applications. With respect to miRNA processing and function, understanding its influence on mRNA targeting and the silencing ability of individual miRNAs, e.g., under pathological conditions, remains a scientific challenge. In the present study, a model system is presented where the influence of the two clinically used anticancer drugs, cisplatin and oxaliplatin, on siRNA's silencing capacity has been evaluated. More specifically, siRNAs targeting the 3' UTR region of Wnt-5a mRNA (NM_003352) were constructed, and the biologically active antisense RNA strand was pre-platinated. Platinum adducts were detected and characterized by a combination of gel electrophoresis and MALDI-MS techniques, and the silencing capacity was evaluated in cellular luciferase-expressing systems using HB2 cells. Data show that platination of the antisense strand of the siRNAs results in adducts with protection against hydrolytic cleavage in the proximity of the platination sites, i.e., with altered degradation patterns compared to native RNAs. The MALDI-MS method was successfully used to further identify and characterize platinated RNA, with the naturally occurring platinum isotopic patterns serving as sensitive fingerprints for metalated sites. Expression assays all confirm biological activity of antisense-platinated siRNAs, here with platination sites located outside of the seed region. A significant reduction of silencing capacity was observed as a general trend, however. Of the two complexes studied, oxaliplatin exhibits the larger influence, thus indicating subtle differences between the abilities of cis- and oxaliplatin to interfere with si- and miRNA processing.

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“…A recent study also demonstrated that cisplatin, oxaliplatin and carboplatin have different effects on mRNA translation in vitro [74]. Moreover, RNA-cisplatin adducts have been shown to inhibit the function of some RNA processing enzymes in vitro [75]. Interestingly, inductively coupled plasma mass spectrometry (ICP-MS) was recently used to show that platinum accumulates in total 4-to 20-fold more in total cellular RNA than in genomic DNA upon cisplatin treatment of Saccharomycie cerevisiae (S. cerevisiae) [76].…”

Section: Platinum Binding To Rnamentioning

confidence: 99%

“…This rapid crosslink formation in an internal loop of a structurally complex RNA may in principle affect RNA dynamics and function [80]. However, the effect of RNA-platinum binding on cell functions is still largely unknown [39,75].…”

Section: Platinum Binding To Structured Rnas: the Case Of Spliceosomamentioning

confidence: 99%

Covalent and non-covalent binding of metal complexes to RNA

Alberti

Zampakou

Donghi

2016

Journal of Inorganic Biochemistry

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Targeting nucleic acids with metal complexes is an exciting and widely explored field of research. Following the discovery of the anticancer drug cisplatin, a number of metal complexes have been designed, synthesised, and tested for their DNA binding properties. On the contrary, the interaction of metal complexes with RNA has been much less investigated. RNA is an essential biomolecule, involved in a variety of crucial cellular functions, which offers a much wider structural diversity than DNA. As such, RNA represents an attractive target for the design and the development of structure-selective therapeutic and diagnostic agents. A few recent publications describe the ability of various metal complexes to interact with RNA, and the binding of cisplatin and derivatives to RNA is being currently investigated. This short review offers an overview of some recent advances on both covalent and non-covalent interactions of metal complexes with RNA and addresses the potential of targeting RNA non-duplex structures.

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Enzymatic Processing of Platinated RNAs

Cited by 34 publications

References 65 publications

Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics

Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics

Platinum Interference with siRNA Non-seed Regions Fine-Tunes Silencing Capacity

Covalent and non-covalent binding of metal complexes to RNA

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