Insights into the mechanism of action of platinum anticancer drugs from multinuclear NMR spectroscopy

Berners‐Price, Susan J.; Ronconi, Luca; Sadler, Peter J.

doi:10.1016/j.pnmrs.2006.05.002

Cited by 166 publications

(273 citation statements)

References 154 publications

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“…A similar behavior was observed in the reaction of apoMnk1 with oxaliplatin, however the reaction appears to be slower: after 3 h incubation only weak signals relative to the monodentate adduct {Pt(R,R-DACH)(oxalateH)} + -Mnk1 are present together with those of apoMnk1; after 24 h, the apoMnk1 signals decrease while intense signals relative to the chelate adduct {Pt(R,R-DACH)} 2+ -Mnk1 appear (Figures 3C and 3D) [8] After 3 h incubation, the intensity of these cross-peaks decreases simultaneously with the appearance of two cross-peaks relative to the intermediate species characterized by one 15 NH 3 trans to Cl and one 15 To prove that cysteine residues of the Cu + -binding motif, CXXC, are involved in Pt coordination, 1 H, 13 C-HSQC spectra were recorded on 15 N, 13 C-Cys Mnk1 incubated with one equivalent of cisplatin ( Figures S3A-C). After 3h incubation, original cross-peaks of apoMnk1 nearly disappear with concomitant appearance of new cross-peaks for α-CH and β-CH 2 groups of Cys15 and Cys18, that correspond to monodentate adduct with the Pt drug (S3B).…”

Section: Platinum Binding To Apomnk1mentioning

confidence: 96%

Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B

et al. 2013

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Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance, a phenomenon not entirely understood, with contribution of drug detoxification, defective accumulation, and efflux from the cell. Downregulation of CTR1, responsible for Cu uptake by the cell, and up-regulation of the Cu-ATPases, ATP7A and ATP7B, which accept Cu from the cytosolic chaperone Atox1 and transfer the metal ion into the secretory pathway where it is incorporated into cuproenzymes, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human CuATPases, we performed electrical measurements on COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, adsorbed on a solid supported

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Section: Platinum Binding To Apomnk1mentioning

confidence: 96%

Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B

et al. 2013

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“…The complexation creates intrastrand crosslinked DNA adducts, preferentially involving two nitrogen atoms belonging to two adjacent G nucleobases or, to a lesser extent, to AG sequences, and leads to apoptosis. [12] The high sensitivity and its ability to provide useful information on geometry and electronic structure of a metal complex makes J-coupling a potentially useful probe in research related to cisplatin-type drugs, at least under in vitro conditions [13][14][15][16][17][18][19][20][21] where the low NMR detection limit at sublethal physiological conditions [13,22] can be bypassed. The properties of cisplatin complexes have also attracted the interest of the theoretical community.…”

Section: Ptàmentioning

confidence: 99%

NMR J‐Coupling Constants in Cisplatin Derivatives Studied by Molecular Dynamics and Relativistic DFT

2011

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Solvent effects on J((195)Pt-(15)N) one-bond nuclear spin-spin coupling constants (J(PtN)) of cisplatin [cis-diamminedichloroplatinum(II)] and three cisplatin derivatives are investigated using a combination of density functional theory (DFT) based ab initio molecular dynamics (aiMD) and all-electron relativistic DFT NMR calculations employing the two-component relativistic zeroth-order regular approximation (ZORA). Good agreement with experiment is obtained when explicit solvent molecules are considered and when the computations are performed with a hybrid functional. Spin-orbit coupling causes only small effects on J(PtN) . Key factors contributing to the magnitude of coupling constants are elucidated, with the most significant being the presence of solvent as well as the quality of the density functional and basis set combination. The solvent effects are of the same magnitude as J(PtN) calculated for gas-phase geometries. However, the trends of J(PtN) among the complexes are already present in the gas phase. Results obtained with a continuum solvent model agree quite well with the aiMD results, provided that the Pt solvent-accessible radius is carefully chosen. The aiMD results support the existence of a partial hydrogen-bond-like inverse-hydration-type interaction affording a weak (1)J(Pt⋅⋅⋅H(w)) coupling between the complexes and the coordinating water molecule.

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“…For example, [ 1 H, 15 N]-HSQC experiments were used to obtain insights into the mechanism of action of platinum drugs, including kinetics and selectivity of DNA platination reactions. [50] Also [ Pt chemical shift range spans thousands of ppm and is particularly sensitive to changes in the coordination sphere. [50] In addition, NMR spectroscopy was used to solve the structure of platinated double stranded DNA as well as to evaluate the intercalative mode of interaction between metal complexes and DNA.…”

Section: Nucleic Acid Interactions With Metal Complexesmentioning

confidence: 99%

“…[50] Also [ Pt chemical shift range spans thousands of ppm and is particularly sensitive to changes in the coordination sphere. [50] In addition, NMR spectroscopy was used to solve the structure of platinated double stranded DNA as well as to evaluate the intercalative mode of interaction between metal complexes and DNA. [50,51] Metal complexes have numerous possible applications, ranging from diagnosis to therapeutics.…”

Section: Nucleic Acid Interactions With Metal Complexesmentioning

confidence: 99%

“…[50] In addition, NMR spectroscopy was used to solve the structure of platinated double stranded DNA as well as to evaluate the intercalative mode of interaction between metal complexes and DNA. [50,51] Metal complexes have numerous possible applications, ranging from diagnosis to therapeutics. [52] Given the increasing importance of RNA as possible alternative molecular target for several drugs, [53] we have recently started as part of an Ambizione Fellowship (to DD) and within the COST Action CM1105 to evaluate the interaction between metal-based drugs and RNA molecules using different techniques, including multinuclear NMR spectroscopy.…”

Section: Nucleic Acid Interactions With Metal Complexesmentioning

confidence: 99%

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NMR Spectroscopy in Bioinorganic Chemistry

Donghi

Johannsen

Sigel

et al. 2012

Chimia

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Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function and structure of large biomolecules. Specifically, NMR is used i) to investigate how metal ions bind to nucleic acids and thereby control the folding and structure of RNAs, ii) to characterize how metal ions are able to stabilize modified nucleic acids to be used as potential nanowires, and iii) to characterize the formation, structure, and role of the diverse metal clusters within plant metallothioneins. In this review we summarize the various NMR experiments applied and the information obtained, demonstrating the important and fascinating part NMR spectroscopy plays in the field of bioinorganic chemistry. NMR Spectroscopy in Bioinorganic ChemistryDaniela Donghi, Silke Johannsen, Roland K. O. Sigel*, and Eva Freisinger* Abstract: Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function and structure of large biomolecules. Specifically, NMR is used i) to investigate how metal ions bind to nucleic acids and thereby control the folding and structure of RNAs, ii) to characterize how metal ions are able to stabilize modified nucleic acids to be used as potential nanowires, and iii) to characterize the formation, structure, and role of the diverse metal clusters within plant metallothioneins. In this review we summarize the various NMR experiments applied and the information obtained, demonstrating the important and fascinating part NMR spectroscopy plays in the field of bioinorganic chemistry.

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Insights into the mechanism of action of platinum anticancer drugs from multinuclear NMR spectroscopy

Cited by 166 publications

References 154 publications

Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B

Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B

NMR J‐Coupling Constants in Cisplatin Derivatives Studied by Molecular Dynamics and Relativistic DFT

NMR Spectroscopy in Bioinorganic Chemistry

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