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More pronounced salt dependence and higher reactivity for platination of the hairpin r(CGCGUUGUUCGCG) compared with d(CGCGTTGTTCGCG)

Hägerlöf, Margareta LU ; Papsai, Pal LU ; Chow, Christine S. and Elmroth, Sofi LU (2006) In Journal of Biological Inorganic Chemistry 11(8). p.974-990
Abstract
The DNA interference pathways exhibited by cisplatin and related anticancer active metal complexes have been extensively studied. Much less is known to what extent RNA interaction pathways may operate in parallel, and perhaps contribute to both antineoplastic activity and toxicity. The present study was designed with the aim of comparing the reactivity of two model systems comprising RNA and DNA hairpins, r(CGCGUUGUUCGCG) and d(CGC GTTGTTCGCG), towards a series of platinum(II) complexes. Three platinum complexes were used as metallation reagents; cis-[ptCl(NH3)(2)(OH2)](+) (1), cis-[PtCl(NH3)(C-C6H11NH2)(OH2)](+) (2), and trans[PtCl(NH3)(quinoline)(OH2)](+) (3). The reaction kinetics were studied at pH 6.0, 25 degrees C, and 1.0 mM < 1:... (More)
The DNA interference pathways exhibited by cisplatin and related anticancer active metal complexes have been extensively studied. Much less is known to what extent RNA interaction pathways may operate in parallel, and perhaps contribute to both antineoplastic activity and toxicity. The present study was designed with the aim of comparing the reactivity of two model systems comprising RNA and DNA hairpins, r(CGCGUUGUUCGCG) and d(CGC GTTGTTCGCG), towards a series of platinum(II) complexes. Three platinum complexes were used as metallation reagents; cis-[ptCl(NH3)(2)(OH2)](+) (1), cis-[PtCl(NH3)(C-C6H11NH2)(OH2)](+) (2), and trans[PtCl(NH3)(quinoline)(OH2)](+) (3). The reaction kinetics were studied at pH 6.0, 25 degrees C, and 1.0 mM < 1: 500 mM. For both types of nucleic acid targets, compound 3 was found to react about 1 order of magnitude more rapidly than compounds 1 and 2. Further, all platinum compounds exhibited a more pronounced salt dependence for the interaction with r(CGCGUUGUUCGCG). Chemical and enzymatic cleavage studies revealed similar interaction patterns with r(CGCGUUGUUCGCG) after long exposure times to 1 and 2. A substantial decrease of cleavage intensity was found at residues G4 and G7, indicative of bifunctional adduct formation. Circular dichroism studies showed that platinum adduct formation leads to a structural change of the ribonucleic acid. Thermal denaturation studies revealed platination to cause a decrease of the RNA melting temperatures by 5-10 degrees C. Our observations therefore suggest that RNA is a kinetically competitive target to DNA. Furthermore, platination causes destabilization of RNA structural elements, which may lead to deleterious intracellular effects on biologically relevant RNA targets. (Less)
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; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA damage, toxicity, anticancer drug, nucleic acid
in
Journal of Biological Inorganic Chemistry
volume
11
issue
8
pages
974 - 990
publisher
Springer
external identifiers
  • wos:000241862400003
  • scopus:33751202702
ISSN
1432-1327
DOI
10.1007/s00775-006-0157-y
language
English
LU publication?
yes
id
122f3868-bbde-47dc-b097-d2f15537b52f (old id 377021)
date added to LUP
2016-04-01 12:36:42
date last changed
2021-04-13 02:08:09
@article{122f3868-bbde-47dc-b097-d2f15537b52f,
  abstract     = {The DNA interference pathways exhibited by cisplatin and related anticancer active metal complexes have been extensively studied. Much less is known to what extent RNA interaction pathways may operate in parallel, and perhaps contribute to both antineoplastic activity and toxicity. The present study was designed with the aim of comparing the reactivity of two model systems comprising RNA and DNA hairpins, r(CGCGUUGUUCGCG) and d(CGC GTTGTTCGCG), towards a series of platinum(II) complexes. Three platinum complexes were used as metallation reagents; cis-[ptCl(NH3)(2)(OH2)](+) (1), cis-[PtCl(NH3)(C-C6H11NH2)(OH2)](+) (2), and trans[PtCl(NH3)(quinoline)(OH2)](+) (3). The reaction kinetics were studied at pH 6.0, 25 degrees C, and 1.0 mM &lt; 1: 500 mM. For both types of nucleic acid targets, compound 3 was found to react about 1 order of magnitude more rapidly than compounds 1 and 2. Further, all platinum compounds exhibited a more pronounced salt dependence for the interaction with r(CGCGUUGUUCGCG). Chemical and enzymatic cleavage studies revealed similar interaction patterns with r(CGCGUUGUUCGCG) after long exposure times to 1 and 2. A substantial decrease of cleavage intensity was found at residues G4 and G7, indicative of bifunctional adduct formation. Circular dichroism studies showed that platinum adduct formation leads to a structural change of the ribonucleic acid. Thermal denaturation studies revealed platination to cause a decrease of the RNA melting temperatures by 5-10 degrees C. Our observations therefore suggest that RNA is a kinetically competitive target to DNA. Furthermore, platination causes destabilization of RNA structural elements, which may lead to deleterious intracellular effects on biologically relevant RNA targets.},
  author       = {Hägerlöf, Margareta and Papsai, Pal and Chow, Christine S. and Elmroth, Sofi},
  issn         = {1432-1327},
  language     = {eng},
  number       = {8},
  pages        = {974--990},
  publisher    = {Springer},
  series       = {Journal of Biological Inorganic Chemistry},
  title        = {More pronounced salt dependence and higher reactivity for platination of the hairpin r(CGCGUUGUUCGCG) compared with d(CGCGTTGTTCGCG)},
  url          = {http://dx.doi.org/10.1007/s00775-006-0157-y},
  doi          = {10.1007/s00775-006-0157-y},
  volume       = {11},
  year         = {2006},
}