Publications by authors named "Julie A Woods"

19 Publications

  • Page 1 of 1

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Dalton Trans 2021 Aug;50(30):10593-10607

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. and Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4. Complexes 1 and 2 showed greater photocytotoxicity than 4 when irradiated with 420 nm light (A2780 cell line IC50 values: 2.7 and 3.7 μM) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 μM). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pKa(H2O) of 5.13 for the free carboxylate group was determined for 1, corresponding to an overall negative charge during biological experiments, which crucially, did not appear to impede cellular accumulation and photocytotoxicity.
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http://dx.doi.org/10.1039/d1dt01730fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335519PMC
August 2021

Platinum(iv) dihydroxido diazido -(heterocyclic)imine complexes are potently photocytotoxic when irradiated with visible light.

Chem Sci 2019 Oct 8;10(37):8610-8617. Epub 2019 Aug 8.

Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email: ; Email: ; Tel: +44 (0)1865 285131.

A series of -di-(-heterocyclic)imine dihydroxido diazido Pt complexes of the form ,,-[Pt(N)(OH)(L)(L)] where L = pyridine, 2-picoline, 3-picoline, 4-picoline, thiazole and 1-methylimidazole have been synthesised and characterised, and their photochemical and photobiological activity evaluated. Notably, complexes (L = py, L = 3-pic) and (L = L = 4-pic) were potently phototoxic following irradiation with visible light (420 nm), with IC values of 4.0 μM and 2.1 μM respectively (A2780 cancer cell line), demonstrating greater potency than the previously reported complex (L = L = py; 6.7 μM); whilst also being minimally toxic in the absence of irradiation. Complexes with mixed -(heterocyclic)imine ligands and (L = py, L = 4-pic) were particularly photocytotoxic towards cisplatin resistant (A2780cis) cell lines. Complex (L = py, L = 2-pic) was comparatively less photocytotoxic (IC value 14.5 μM) than the other complexes, despite demonstrating the greatest absorbance at the irradiation wavelength and the fastest half-life for loss of the N → Pt LMCT transition upon irradiation ( = 463 nm) in aqueous solution. Complex (X = X = thiazole) although potently phototoxic (2.4 μM), was also toxic towards cells in the absence of irradiation.
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http://dx.doi.org/10.1039/c9sc02644dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844273PMC
October 2019

A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin.

Chemistry 2015 Dec 2;21(50):18474-86. Epub 2015 Nov 2.

Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).

A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.
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http://dx.doi.org/10.1002/chem.201502373DOI Listing
December 2015

An integrin-targeted photoactivatable Pt(IV) complex as a selective anticancer pro-drug: synthesis and photoactivation studies.

Chem Commun (Camb) 2015 Jun;51(44):9169-72

Departament de Química Orgànica and IBUB, Universitat de Barcelona, Barcelona, E-08028, Spain.

A new anticancer agent based on the conjugation of a photoactivatable Pt(IV) pro-drug to a cyclic RGD-containing peptide is described. Upon visible light irradiation, phototoxicity was induced preferentially in SK-MEL-28 melanoma cancer cells overexpressing αVβ3 integrin compared to control DU-145 human prostate carcinoma cells.
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http://dx.doi.org/10.1039/c5cc03180jDOI Listing
June 2015

The effect of 222-nm UVC phototesting on healthy volunteer skin: a pilot study.

Photodermatol Photoimmunol Photomed 2015 May 15;31(3):159-66. Epub 2015 Jan 15.

Photobiology Unit, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK.

Background: Frequent topical antiseptic use to hands is now common in healthcare and other work environments. Inevitably, the use of such antiseptics will present an occupational risk for irritancy and allergic dermatitis. New, less irritant and even non-chemical antimicrobial approaches are under investigation.

Methods: A Sterilray disinfectant source (222 nm) conventionally used to sterilize equipment and work surfaces was assessed for tolerability in human skin. Using an escalating dosage study methodology, four skin phototype I and II healthy volunteers had their minimal erythema dose (MED) determined. Punch biopsies of irradiated sites were stained for cyclobutane pyrimidine dimers (CPD). The degree of CPD was compared with that in biopsies from unexposed skin and from areas exposed to UVB (280-315 nm) radiation.

Results: Calibrated spectral measurements revealed emission at a peak wavelength of 222 nm with 97% emission at wavelengths less than 250 nm. At low doses below the threshold bacteriostatic effect, the source was capable of inducing both erythema and CPD formation in human skin. In two individuals, cells in the basal layer were not shielded by the overlying tissue as indicated by the presence of CPD.

Conclusion: The source showed an erythemogenic or CPD potential at lower doses than those required to reach the reported threshold bacteriostatic effect.
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http://dx.doi.org/10.1111/phpp.12156DOI Listing
May 2015

Cellular accumulation, lipophilicity and photocytotoxicity of diazido platinum(IV) anticancer complexes.

ChemMedChem 2014 Jun 19;9(6):1169-75. Epub 2014 May 19.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL (UK); IMDEA Nanoscience, C/ Faraday 9, Cantoblanco, 28049 Madrid (Spain).

The lipophilicity of ten photoactivatable platinum(IV) diazido prodrugs of formula trans,trans,trans-[Pt(N3 )2 (OH)2 (R)(R')] (where R and R' are NH3 , methylamine, ethylamine, pyridine, 2-picoline, 3-picoline or thiazole) has been determined by their retention times on reversed-phase HPLC. The lipophilicity of the complexes shows a linear dependence on the lipophilicity (partition coefficient) of the ligands. Accumulation of platinum in A2780 human ovarian cancer cells after one hour drug exposure in the dark is compared with their cytotoxic potency on activation with UVA (365 nm) and to their lipophilicity. No correlation between lipophilicity and intracellular accumulation of platinum was observed, perhaps suggesting involvement of active transport and favoured influx of selected structures. Furthermore, no correlation between platinum accumulation and photocytotoxicity was observed in A2780 cancer cells, implying that the type of intracellular damage induced by these complexes plays a key role in their cytotoxic effects.
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http://dx.doi.org/10.1002/cmdc.201402066DOI Listing
June 2014

Cytochrome P450 CYP1B1 interacts with 8-methoxypsoralen (8-MOP) and influences psoralen-ultraviolet A (PUVA) sensitivity.

PLoS One 2013 23;8(9):e75494. Epub 2013 Sep 23.

Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, United Kingdom ; School of Contemporary Science, University of Abertay Dundee, Dundee, United Kingdom.

Background: There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression.

Objectives: We investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity.

Methods: We used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity.

Results: We showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-β-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxic metabolite(s).

Conclusion: Our data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781062PMC
July 2014

Differential sensitivity in cell lines to photodynamic therapy in combination with ABCG2 inhibition.

J Photochem Photobiol B 2013 Sep 10;126:87-96. Epub 2013 Jul 10.

Photobiology Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, United Kingdom.

Background: ABCG2 is an ATP-binding cassette transporter protein which has a role in the regulation of endogenous protoporphyrin IX (PpIX) levels.

Objective: To understand the influence of ABCG2 on porphyrin-based photodynamic therapy (PDT) and fluorescence diagnosis (FD), we examined the role of endogenous ABCG2 in four human cell lines from the epidermis (HaCaT keratinocytes), oesophagus (OE19 adenocarcinoma), brain (SH-SY5Y neuroblastoma) and bladder (HT1197 carcinoma).

Methods: Cells were incubated with ALA or MAL in the presence or absence of the ABCG2 activity inhibitor Ko-143. Porphyrin accumulation was detected by spectrofluorimetric analysis and high performance liquid chromatography (HPLC) with porphyrin localisation observed by confocal laser scanning microscopy. PDT efficacy was assessed 24h post irradiation (1.5J/cm(2) red light) by the neutral red (NR) assay.

Results: We show cell-specific differences when Ko-143 was co-incubated with ALA or, in particular with, MAL. Enhanced PDT-induced cell kill was shown in HaCaT, OE19 and HT1197 cells, but not SH-SY5Y cells and could be explained by porphyrin accumulation and expression of ABCG2. We have also found that despite high levels of intracellular PpIX, the OE19 cells were protected from phototoxic cell death by PpIX compartmentalisation. This could be reversed by Ko-143.

Conclusion: The results from this study show a possible cause of reduced sensitivity to ALA/MAL-PDT, with a potential solution to overcome this effect in certain tissue types. The potential to improve PDT with Ko-143 remains promising.
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http://dx.doi.org/10.1016/j.jphotobiol.2013.07.003DOI Listing
September 2013

Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts.

Chemistry 2013 Jul 3;19(29):9578-91. Epub 2013 Jun 3.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable Pt(IV) prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N3)2(OH)2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans-[Pt(N3)2(OH)2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1p and 1q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross-linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the Pt(II) compounds trans-[PtCl2(MA)(Py)] (5) and trans-[PtCl2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation.
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http://dx.doi.org/10.1002/chem.201300374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280898PMC
July 2013

Tryptophan switch for a photoactivated platinum anticancer complex.

J Am Chem Soc 2012 Oct 25;134(40):16508-11. Epub 2012 Sep 25.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

The octahedral Pt(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(py)(2)] (1) is potently cytotoxic to cancer cells when irradiated with visible (blue) light. We show that the acute photocytotoxicity can be switched off by low doses (500 μM) of the amino acid l-tryptophan. EPR and NMR spectroscopic experiments using spin traps show that l-Trp quenches the formation of azidyl radicals, probably by acting as an electron donor. l-Trp is well-known as a mediator of electron transfer between distant electron acceptor/donor centers in proteins, and such properties may make the free amino acid clinically useful for controlling the activity of photochemotherapeutic azido Pt(IV) drugs. Since previous work has demonstrated the ability of photoactivated 1 to platinate DNA, this suggests that the high potency of such photoactive platinum complexes is related to their dual attack on cancer cells by radicals and Pt(II) photoproducts.
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http://dx.doi.org/10.1021/ja3074159DOI Listing
October 2012

Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light-activated antitumor platinum complex that kills human cancer cells by an apoptosis-independent mechanism.

Mol Cancer Ther 2012 Sep 18;11(9):1894-904. Epub 2012 Jun 18.

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany.

Photoactivatable Pt(IV) diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC(50) value in 13 cell lines of 55 ± 28 μmol/L after 30 minutes (0.12 mW/cm(2)) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated complex 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of complex 3 have been obtained from (14)N{(1)H} nuclear magnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3, which gives rise to reactive, possibly cytotoxic azidyl radicals.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521251PMC
September 2012

Characterization of a human keratinocyte HaCaT cell line model to study the regulation of CYP2S1.

Drug Metab Dispos 2012 Feb 28;40(2):283-9. Epub 2011 Oct 28.

Centre for Neuroscience, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

CYP2S1 is an extrahepatic cytochrome P450 (P450) that shows marked individuality in constitutive and inducible expression. CYP2S1 mRNA expression is increased in psoriasis and by treatments for psoriasis, including retinoids and UV radiation, although endogenous substrates remain poorly characterized. Because previous model systems have overexpressed modified CYP2S1 in bacteria, human HaCaT keratinocyte cells were screened for constitutive and regulatable CYP2S1 expression and CYP2S1 activity in HaCaT cells compared with a novel Chinese hamster ovary (CHO)-based cell line engineered to stably coexpress CYP2S1 and NADPH cytochrome P450 reductase. Constitutive mRNA expression for CYP2S1 and additional P450s, retinoid acid receptors (RARα, RARβ, RARγ), and retinoid X receptors (RXRα, RXRβ and RXRγ) was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis in HaCaT cells. Cells were then exposed to retinoids or to UV radiation (UVR), and changes in CYP2S1 mRNA abundance were further examined by qRT-PCR analysis. P450 expression in HaCaT cells was similar to human skin, with abundant CYP2S1 expression. RARα and RARγ (but not RARβ) and all RXR isoforms were also detectable. All-trans retinoic acid (atRA) induced CYPS1 mRNA expression more potently than 9-cis RA or 13-cis RA. P450-dependent atRA metabolism was demonstrated in HaCaT cells, with a very similar metabolite profile to that produced by our CYP2S1-expressing CHO cells. CYP2S1 mRNA expression was also induced by UVR, more potently than CYP1B1, a known UVR-inducible P450. Our results demonstrate regulatable and functional CYP2S1 expression in HaCaT cells, thus identifying a human cell line model with utility for further analysis of CYP2S1 regulation and substrate specificity.
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http://dx.doi.org/10.1124/dmd.111.042085DOI Listing
February 2012

A potent trans-diimine platinum anticancer complex photoactivated by visible light.

Angew Chem Int Ed Engl 2010 Nov;49(47):8905-8

Department of Chemistry, University of Warwick, Warwick, CV4 7AL Coventry, UK.

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http://dx.doi.org/10.1002/anie.201003399DOI Listing
November 2010

Photocytotoxic trans-diam(m)ine platinum(IV) diazido complexes more potent than their cis isomers.

Chem Res Toxicol 2010 Feb;23(2):413-21

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.

The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N(3))(2)(OH)(2)(NH(3))(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis-trans isomerism has been investigated. A series of photoactivatable Pt(IV)-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine Pt(IV) diazido complexes, cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-Pt(IV) LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the Pt(IV) complexes undergo photoreduction to Pt(II) species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH(3) ligands by MeNH(2) or EtNH(2) results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.
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http://dx.doi.org/10.1021/tx900372pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933822PMC
February 2010

A potent cytotoxic photoactivated platinum complex.

Proc Natl Acad Sci U S A 2007 Dec 19;104(52):20743-8. Epub 2007 Dec 19.

School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.

We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(py)] (1) contains an octahedral Pt(IV) center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the Pt(II) anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt(II) adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido Pt(IV) complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.
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http://dx.doi.org/10.1073/pnas.0707742105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410072PMC
December 2007

A photoactivated trans-diammine platinum complex as cytotoxic as cisplatin.

Chemistry 2006 Apr;12(11):3155-61

School of Chemistry, The University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3 JJ, UK.

The synthesis and X-ray structure (as the tetrahydrate) of the platinum(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 3 are described and its photochemistry and photobiology are compared with those of the cis isomer cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] 4. Complexes 4 and 3 are potential precursors of the anticancer drug cisplatin and its inactive trans isomer transplatin, respectively. The trans complex 3 is octahedral, contains almost linear azide ligands, and adopts a layer structure with extensive intermolecular hydrogen bonding. The intense azide-to-platinum(IV) charge-transfer band of complex 3 (285 nm; epsilon=19 500 M(-1) cm(-1)) is more intense and bathochromically shifted relative to that of the cis isomer 4. In contrast to transplatin, complex 3 rapidly formed a platinum(II) bis(5'-guanosine monophosphate) (5'-GMP) adduct when irradiated with UVA light, and did not react in the dark. Complexes 3 and 4 were non-toxic to human skin cells (keratinocytes) in the dark, but were as cytotoxic as cisplatin on irradiation for a short time (50 min). Damage to the DNA of these cells was detected by using the "comet" assay. Both trans- and cis-diammine platinum(IV) diazide complexes therefore have potential as photochemotherapeutic agents.
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http://dx.doi.org/10.1002/chem.200501601DOI Listing
April 2006

Pilot screening programme for small molecule activators of p53.

Int J Cancer 2005 Jul;115(5):701-10

Department of Surgery and Molecular Oncology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.

Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way to long-term and possibly prophylactic treatments. We have established a simple protocol to screen small compound libraries for activators of p53-dependent transcription, and to select and characterise the most interesting hits, which include non-genotoxic activators. These compounds or their derivatives are of potential clinical interest. This approach may also lead to the identification of novel p53-activating compound families and possibly to the description of novel molecular pathways regulating p53 activity.
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http://dx.doi.org/10.1002/ijc.20968DOI Listing
July 2005

Use of Tween 40 and Tween 80 to deliver a mixture of phytochemicals to human colonic adenocarcinoma cell (CaCo-2) monolayers.

Br J Nutr 2004 May;91(5):757-64

Department of Food and Nutritional Sciences, University College, Cork, Republic of Ireland.

Epidemiological evidence suggests that dietary intake of carotenoids and tocopherols may influence the risk of certain chronic diseases, such as cancer and CVD. In vitro studies investigating the synergistic effects of mixtures of carotenoids and tocopherols have been hindered due to the difficulty of solubilising these lipophilic compounds. The objective of the present study was to develop a system for delivering tocopherols and carotenoids simultaneously to cells in culture. Differentiated human colonic adenocarcinoma cells (CaCo-2) were incubated with a mixture of these phytochemicals for 24 h. The phytochemical mixture included carotenoids (astaxanthin, canthaxanthin, lutein, lycopene, alpha-carotene, beta-carotene) and tocopherols (alpha-tocopherol and gamma-tocopherol). The emulsifiers polyoxyethylene sorbitan monopalmitate (Tween 40) and polyoxyethylene sorbitan monooleate (Tween 80) were employed as the delivery vehicles, and were compared with tetrahydrofuran (THF). Each vehicle was added at a maximum concentration of 1 ml/l. No toxic effects to the CaCo-2 cells were noted when Tween 40 or Tween 80 were used. Both Tween 40 and Tween 80 resulted in greater solubility of the mixture and delivered substantially more carotenoids and tocopherols to the cells than THF. In particular, lycopene was detected within the cells when Tween 40 and Tween 80 were employed, whereas it was below the limits of detection by HPLC when THF was used as the delivery vehicle. The phytochemicals were retained within the cells for 24 h after supplementation. Tween 40 and Tween 80 have potential as simple, rapid and non-toxic methods for delivering mixtures of carotenoids and tocopherols to cells in culture.
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http://dx.doi.org/10.1079/BJN20041094DOI Listing
May 2004

Genotoxicity of fecal water in a free-living Irish population.

Nutr Cancer 2002 ;42(1):62-9

Department of Food Science, Food Technology, and Nutrition, University College, Cork, Republic of Ireland.

The alkaline single-cell gel electrophoresis (comet) assay was used to investigate the genotoxicity of fecal water (FW) isolated from 47 Irish subjects using Caco-2 colonocytes as target cells. Two methods of comet assay analysis were compared to determine the extent of DNA damage and to categorize the samples as having no, low-to-moderate, or high genotoxicity. FW was isolated from stool samples by centrifugation and tested for its ability to induce DNA damage in Caco-2 cells. DNA damage was assessed using the comet assay by measuring the extent of DNA migration from the nucleus (microns, tail length) or by classifying the nuclei into five different categories depending on their morphology. Data collected from the two methods were used to categorize the FW samples on the basis of their genotoxic activity. Both methods showed good agreement. There was an approximately 50:50 split, with half the samples having some level of genotoxic activity and half having no genotoxicity. About one-third of the samples were considered to be highly genotoxic. There was a trend for low pH of the FW to be associated with increased DNA damage, but this was not significant. The results presented in this report show a relatively high incidence of genotoxic FW in samples derived from a free-living Irish population. Our data demonstrate the suitability of classifying nuclei on the basis of their morphology as a means of determining DNA damage. This procedure is very rapid and, therefore, advantageous in analyzing a large number of slides in the absence of an image analysis system.
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http://dx.doi.org/10.1207/S15327914NC421_9DOI Listing
January 2003
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