Chromium(III) complexes inhibit transcription factors binding to DNA and associated gene expression

Sella, Raja Natesan; Nair, Balachandran Unni

doi:10.1016/j.tox.2008.07.052

Cited by 38 publications

(15 citation statements)

References 43 publications

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“…An in vitro analysis of the effect of ion partner on DNA conformation showed that heavy metals may induce severe conformational changes of the double helix (Duguid et al, 1993). There is also an evidence that interaction of heavy metals with the double helix may impair relationships between DNA and nuclear proteins; for example, Cr 3+ complexes are able to bind to large groove in DNA, blocking its availability for transcription factors and thus inhibiting gene expression (Raja & Nair, 2008).…”

Section: Introductionmentioning

confidence: 99%

Heavy metals in the cell nucleus - role in pathogenesis

Sas–Nowosielska

Pawlas

2015

Acta Biochim Pol

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People are exposed to heavy metals both in an occupational and natural environment. The most pronounced effects of heavy metals result from their interaction with cellular genetic material packed in form of chromatin. Heavy metals influence chromatin, mimicking and substituting natural microelements in various processes taking place in the cell, or interacting chemically with nuclear components: nucleic acids, proteins and lipids. This paper is a review of current knowledge on the effects of heavy metals on chromatin, exerted at the level of various nuclear components.

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Section: Introductionmentioning

confidence: 99%

Heavy metals in the cell nucleus - role in pathogenesis

Sas–Nowosielska

Pawlas

2015

Acta Biochim Pol

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“…Transcription inhibition is observed with certain organometallic complexes [17][18][19][20][21][22][23][24][25][26][27] and we sought to examine this process as a possible mechanism for the cytotoxic behavior of the corrole family. This transcription assay provides a straightforward, inexpensive, and facile method for assessing transcription inhibition, which will lead to more detailed information about the effects of these molecules in live cells.…”

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confidence: 99%

“…Corrole inhibition of RNA transcription would offer greater insight on their interactions with biomacromolecules. Other complexes known to bind to DNA, such as dirhodium(II,II) complexes, chromium(III) complexes, ruthenium(II) polypyridyl complexes, rhodium(III) complexes, and various others, were subjected to RNA transcription assays, [18][19][20][21][22][23][24][25][26][27] resulting in greater understanding of their interactions with biomacromolecules. This facile and widely available experiment is also a good initial test to assess the cytotoxicity properties of a given molecule and determine whether it merits further biological testing.…”

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confidence: 99%

An <em>In Vitro</em> Enzymatic Assay to Measure Transcription Inhibition by Gallium(III) and H<sub>3</sub> 5,10,15-tris(pentafluorophenyl)corroles

Tang

Pribisko

Henning

et al. 2015

JoVE

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Chemotherapy often involves broad-spectrum cytotoxic agents with many side effects and limited targeting. Corroles are a class of tetrapyrrolic macrocycles that exhibit differential cytostatic and cytotoxic properties in specific cell lines, depending on the identities of the chelated metal and functional groups. The unique behavior of functionalized corroles towards specific cell lines introduces the possibility of targeted chemotherapy.Many anticancer drugs are evaluated by their ability to inhibit RNA transcription. Here we present a step-by-step protocol for RNA transcription in the presence of known and potential inhibitors. The evaluation of the RNA products of the transcription reaction by gel electrophoresis and UVVis spectroscopy provides information on inhibitive properties of potential anticancer drug candidates and, with modifications to the assay, more about their mechanism of action.Little is known about the molecular mechanism of action of corrole cytotoxicity. In this experiment, we consider two corrole compounds: gallium(III) 5,10,15-(tris)pentafluorophenylcorrole (Ga(tpfc)) and freebase analogue 5,10,15-(tris)pentafluorophenylcorrole (tpfc). An RNA transcription assay was used to examine the inhibitive properties of the corroles. Five transcription reactions were prepared: DNA treated with Actinomycin D, triptolide, Ga(tpfc), tpfc at a [complex]:[template DNA base] ratio of 0.01, respectively, and an untreated control.The transcription reactions were analyzed after 4 hr using agarose gel electrophoresis and UV-Vis spectroscopy. There is clear inhibition by Ga(tpfc), Actinomycin D, and triptolide.This RNA transcription assay can be modified to provide more mechanistic detail by varying the concentrations of the anticancer complex, DNA, or polymerase enzyme, or by incubating the DNA or polymerase with the complexes prior to RNA transcription; these modifications would differentiate between an inhibition mechanism involving the DNA or the enzyme. Adding the complex after RNA transcription can be used to test whether the complexes degrade or hydrolyze the RNA. This assay can also be used to study additional anticancer candidates.

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“…[12,13] The metallointercalator [L-1-Rh III (MGP) 2 (phi)] 5+ (MGP = methylguanidium phenanthroline, phi = phenanthrenequinone diimine) and the electrostatic surface binder [Cr III (salen)(H 2 O) 2 ] + (salen = N,N'-bis-(salicylidene)ethylenediamine) are rare examples of metal complexes that intercalate DNA in the major groove and inhibit binding of transcription factors AP-1 and Sp1 to their respective consensus DNA sequences. [14] More recently, [Ru II (phen) 2 (dppz)] 2+ and [Pt II (5,6-Me 2 phen)(S,S-dach)] 2+ (phen = 1,10-phenanthroline, dppz = dipyrido[3,2-a:2',3'c]phenazine, Me 2 phen = dimethyl-1,10-phenanthroline, dach = diaminocyclohexane) were found to interfere with the interaction between the transcription factor PU.1 and DNA. [15] The cAMP response element binding protein (CREB) is a well-characterized transcription factor of the basic leucine zipper family.…”

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confidence: 99%