Anticancer drug impact on DNA – a study by neutron spectroscopy coupled with synchrotron-based FTIR and EXAFS

Carvalho, Ana L. M. Batista de; Mamede, A. P.; Dopplapudi, Asha; Sakai, Victoria García; Doherty, James; Frogley, Mark D.; Cinque, Gianfelice; Gardner, Peter; Gianolio, Diego; Carvalho, Luís A. E. Batista de; Marques, M. P. M.

doi:10.1039/c8cp05881d

Cited by 29 publications

(46 citation statements)

References 64 publications

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“…Using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS), and Fourier-transform infrared spectroscopy-attenuated total reflectance (SR-FTIR-ATR), Batista de Carvalho et al studied the effect of Pt/Pd drugs on the structure of DNA. Far-and mid-infrared measurements allowed for confirming changes in DNA conformation owing to interactions with a chemotherapeutic drug [49].…”

Section: Dna Lesions Studied By Spectroscopic Methodsmentioning

confidence: 99%

Molecular Spectroscopic Markers of DNA Damage

Sofińska¹,

Wilkosz²,

Szymoński³

et al. 2020

Molecules

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Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids. Cellular DNA lesions are the most dangerous because the genetic information, critical for the identity and function of each eukaryotic cell, is stored in the DNA. In this review, we describe spectroscopic markers of DNA damage, which can be detected by infrared, Raman, surface-enhanced Raman, and tip-enhanced Raman spectroscopies, using data acquired from DNA solutions and mammalian cells. Various physical and chemical DNA damaging factors are taken into consideration, including ionizing and non-ionizing radiation, chemicals, and chemotherapeutic compounds. All major spectral markers of DNA damage are presented in several tables, to give the reader a possibility of fast identification of the spectral signature related to a particular type of DNA damage.

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Section: Dna Lesions Studied By Spectroscopic Methodsmentioning

confidence: 99%

Molecular Spectroscopic Markers of DNA Damage

Sofińska¹,

Wilkosz²,

Szymoński³

et al. 2020

Molecules

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“…H 2 O-and D 2 O-hydrated DNA were prepared at a r.h. >80%, to ensure the stability of the native B conformation, with a complete primary hydration shell, yielding the samples now denoted as H 2 O-DNA hyd and D 2 O-DNA hyd , respectively. This was achieved following a previously reported procedure [12]: the DNA was placed in a desiccator (closed environment) with a saturated KCl solution (in either H 2 O or D 2 O) until attaining a stable weight (corresponding to a r.h. of 83.62-84.34%, at 25 • C).…”

Section: Preparation Of Drug-dna Samplesmentioning

confidence: 99%

“…As suggested in previous studies by the authors [12,15,16,19], apart from the conventional targets of these type of metal-based agents (DNA and specific proteins), there may be other receptors that are relevant for chemotherapeutic activity, namely water molecules-both within the cytoplasm and the hydration layers of biomolecules. Intracellular water (cytoplasmic), which accounts for 70 to 80% of the whole cell mass, has a particular structural and dynamical behaviour namely its ability to form highly organised H-bond networks.…”

Section: Introductionmentioning

confidence: 98%

“…Cytotoxicity arises from the selective covalent binding of the metal ions to DNA purine bases at more than one site within the double helix, yielding long-range interstrand adducts. These agents have been synthesised and extensively investigated by the team, to provide a comprehensive set of data on (i) cytotoxicity towards several human cancer cells [6][7][8][9][10], (ii) interactions with DNA and glutathione-mediated resistance pathways [11,12] and (iii) impact on cellular metabolism and intracellular water [12][13][14][15][16]. Vibrational spectroscopy techniques were applied (including inelastic neutron scattering and synchrotron radiation-Fourier transform infrared (FTIR)) coupled to theoretical simulations [4,17,18], as well as synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS) [11].…”

Section: Introductionmentioning

confidence: 99%

“…Translational modes of water are changed near the biopolymers and appear in a different energy transfer range to the vibrations from the biomolecule itself, thus rendering INS a very useful tool to probe water. QENS, in turn, is a method of choice for directly accessing different spatially resolved dynamical processes of key biological components-from fast localised modes to slower global translations-and the way they are changed by the presence of a drug, [12,15,16,19,26,[35][36][37][38][39][40][41][42][43]. While QENS is a direct probe of water's dynamical behaviour, INS and the optical vibrational techniques Raman and FTIR indirectly monitor water properties which affect the corresponding vibrational profile while detecting conformational rearrangements of the biomolecule.…”

Section: Introductionmentioning

confidence: 99%

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A New Look into the Mode of Action of Metal-Based Anticancer Drugs

et al. 2020

Self Cite

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The mode of action of Pt- and Pd-based anticancer agents (cisplatin and Pd2Spm) was studied by characterising their impact on DNA. Changes in conformation and mobility at the molecular level in hydrated DNA were analysed by quasi-elastic and inelastic neutron scattering techniques (QENS and INS), coupled to Fourier transform infrared (FTIR) and microRaman spectroscopies. Although INS, FTIR and Raman revealed drug-triggered changes in the phosphate groups and the double helix base pairing, QENS allowed access to the nanosecond motions of the biomolecule’s backbone and confined hydration water within the minor groove. Distinct effects were observed for cisplatin and Pd2Spm, the former having a predominant effect on DNA’s spine of hydration, whereas the latter had a higher influence on the backbone dynamics. This is an innovative way of tackling a drug’s mode of action, mediated by the hydration waters within its pharmacological target (DNA).

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Blocking ACAT‐1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer‐Encapsulated Avasimible

Bai

Zhu

Shao

et al. 2020

Macromolecular Bioscience

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Targeting the distinct cholesterol metabolism of tumor cells is proposed as a novel way to treat tumors. Blocking acyl‐CoA cholesterol acyltransferase‐1 (ACAT‐1) by the inhibitor avasimible (Ava), which elevates intracellular free cholesterol levels, is shown to effectively induce apoptosis. However, Ava faces disadvantages of poor water solubility, a short half‐life, and no capability for fluorescence detection, which have greatly limited its application. Herein, a fluorescent hyperstar polymer (FHSP) is developed to encapsulate Ava to improve its ability to inhibit HeLa cells and K562 cells. The results of this study show that the obtained Ava–FHSP micelles possess a high drug loading capacity of 22.7% and bright green fluorescence. Ava and Ava–FHSP are cytotoxic to both HeLa and K562 cells and cause reductions in cell size, nuclear lysis, and chromatin condensation and hindered proliferation of both cell types by causing S phase cell cycle arrest. Further mechanistic analysis indicates that Ava–FHSP reduces the protein and messenger RNA expression of ACAT‐1 and significantly increases intracellular free cholesterol levels, which can increase endoplasmic reticulum stress and finally cause cell apoptosis. All these results suggest that this fluorescent hyperstar polymer represents a potential therapeutic tumor strategy by changing the cholesterol metabolism of tumor cells.

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Anticancer drug impact on DNA – a study by neutron spectroscopy coupled with synchrotron-based FTIR and EXAFS

Abstract: Complementary information on drug–DNA interplay has been achieved for Pt/Pd anticancer agents, by a combined QENS, SR-FTIR-ATR and EXAFS approach.

Cited by 29 publications

References 64 publications

Molecular Spectroscopic Markers of DNA Damage

Molecular Spectroscopic Markers of DNA Damage

A New Look into the Mode of Action of Metal-Based Anticancer Drugs

Blocking ACAT‐1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer‐Encapsulated Avasimible

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