Immediate Protein Targets of Photodynamic Treatment in Carcinoma Cells

Tsaytler, Pavel; O’Flaherty, Martina; Sakharov, D.V.; Krijgsveld, Jeroen; Egmond, Maarten R.

doi:10.1021/pr800189q

Cited by 36 publications

(33 citation statements)

References 36 publications

(76 reference statements)

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“…An immediate consequence of the PDT reaction is the generation of singlet oxygen, which, through propagation of redox reactions, results in the oxidation of intracellular proteins 26. One of the specific targets of the photoreaction is the covalent cross-linking of the latent signal-transducing protein STAT-3 in the cytoplasm 27…”

Section: Resultsmentioning

confidence: 99%

Conjugation of 2-(1′-Hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to Carbohydrates Changes its Subcellular Distribution and Enhances Photodynamic Activity in Vivo

Zheng¹,

Morgan²,

Pandey³

et al. 2009

J. Med. Chem.

109

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The carbohydrate moieties on conjugating with 3-(1′-hexyloxyethyl)-3-devinyl pyropeophorbide-a (HPPH) altered the uptake and intracellular localization from mitochondria to lysosomes. In vitro, HPPH-Gal 9 PDT showed increased PDT efficacy over HPPH-PDT as detectable by the oxidative cross-linking of nonphosphorylated STAT3 and cell killing in ABCG2-expressing RIF cells but not in ABCG2-negative Colon26 cells. This increased efficacy in RIF cells could at least partially be attributed to increased cellular accumulation of 9, suggesting a role of the ABCG2 transporter for which HPPH is a substrate. While such differences in the accumulation in HPPH derivatives by tumor tissue in vivo were not detectable, 9 still showed an elevated light dose-dependent activity compared to HPPH in mice bearing RIF as well as Colon26 tumors. Further optimization of the carbohydrate conjugates at variable treatment parameters in vivo is currently underway.

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Section: Resultsmentioning

confidence: 99%

Conjugation of 2-(1′-Hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to Carbohydrates Changes its Subcellular Distribution and Enhances Photodynamic Activity in Vivo

Zheng¹,

Morgan²,

Pandey³

et al. 2009

J. Med. Chem.

109

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“…A more comprehensive proteomics study by Tsaytler et al . 55 used selective biotinylation, affinity purification and MS analysis to identify 314 carbonylated or Cys-oxidized proteins in A431 tumor cells treated with phthalocyanine (Pc4)-mediated PDT. Of them, 66 were also found as severely Met-oxidized proteins in our current study, including GRP78, annexin A1, EGFR, heat shock proteins, etc.…”

Section: Discussionmentioning

confidence: 99%

Oxidation of protein-bound methionine in Photofrin-photodynamic therapy-treated human tumor cells explored by methionine-containing peptide enrichment and quantitative proteomics approach

Hsieh

Chien

Yang

et al. 2017

Sci Rep

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In Photofrin-mediated photodynamic therapy (PDT), cell fate can be modulated by the subcellular location of Photofrin. PDT triggers oxidative damage to target cells, including the methionine (Met) oxidation of proteins. Here, we developed a new Met-containing peptide enrichment protocol combined with SILAC-based quantitative proteomics, and used this approach to explore the global Met oxidation changes of proteins in PDT-treated epidermoid carcinoma A431 cells preloaded with Photofrin at the plasma membrane, ER/Golgi, or ubiquitously. We identified 431 Met-peptides corresponding to 302 proteins that underwent severe oxidation upon PDT and observed overrepresentation of proteins related to the cell surface, plasma membrane, ER, Golgi, and endosome under all three conditions. The most frequently oxidized Met-peptide sequence was “QAMXXMM-E/G/M-S/G-A/G/F-XG”. We also identified several hundred potential Photofrin-binding proteins using affinity purification coupled with LC-MS/MS, and confirmed the bindings of EGFR and cathepsin D with Photofrin. The enzyme activities of both proteins were significantly reduced by Photofrin-PDT. Our results shed light on the global and site-specific changes in Met-peptide oxidation among cells undergoing Photofrin-PDT-mediated oxidative stress originating from distinct subcellular sites, and suggest numerous potential Photofrin-binding proteins. These findings provide new insight into the molecular targets through which Photofrin-PDT has diverse effects on target cells.

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“…A review from tabulated major molecular events during apoptotic death induced by PDT [59], contained 181 references, covering 20 different 'major' cellular events, and this was selective. Large studies looking at proteome changes post PDT highlight the scale and number of pathways involved [60,61]. Pathways that are commonly manipulated by PDT alongside apoptosis, necrosis and autophagy, include the unfolded protein response, calcium homeostasis, lipid metabolism/ceramide signalling, transcriptional regulation including NF-κB signalling, tyrosine kinase signalling including mitogen-activated protein kinases (MAPK), Cyclin-dependent kinases (CDK) and cell cycle control, heat shock protein expression, ROS and antioxidant pathways, hypoxia induced pathways and DNA-damage associated signalling.…”

Section: Pdt Mechanismsmentioning

confidence: 99%

Antibody-Directed Phototherapy (ADP)

et al. 2013

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Photodynamic therapy (PDT) is a clinically-approved but rather under-exploited treatment modality for cancer and pre-cancerous superficial lesions. It utilises a cold laser or LED to activate a photochemical reaction between a light activated drug (photosensitiser-drug) and oxygen to generate cytotoxic oxygen species. These free radical species damage cellular components leading to cell death. Despite its benefits, the complexity, limited potency and side effects of PDT have led to poor general usage. However, the research area is very active with an increasing understanding of PDT-related cell biology, photophysics and significant progress in molecular targeting of disease. Monoclonal antibody therapy is maturing and the next wave of antibody therapies includes antibody-drug conjugates (ADCs), which promise to be more potent and curable. These developments could lift antibody-directed phototherapy (ADP) to success. ADP promises to increase specificity and potency and improve drug pharmacokinetics, thus delivering better PDT drugs whilst retaining its other benefits. Whole antibody conjugates with first generation ADP-drugs displayed problems with aggregation, poor pharmacokinetics and loss of immuno-reactivity. However, these early ADP-drugs still showed improved selectivity and potency. Improved PS-drug chemistry and a variety of conjugation strategies have led to improved ADP-drugs with retained antibody and PS-drug function. More recently, recombinant antibody fragments have been used to deliver ADP-drugs with superior drug loading, more favourable pharmacokinetics, enhanced potency and target cell selectivity. These improvements offer a promise of better quality PDT drugs

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Immediate Protein Targets of Photodynamic Treatment in Carcinoma Cells

Cited by 36 publications

References 36 publications

Conjugation of 2-(1′-Hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to Carbohydrates Changes its Subcellular Distribution and Enhances Photodynamic Activity in Vivo

Conjugation of 2-(1′-Hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to Carbohydrates Changes its Subcellular Distribution and Enhances Photodynamic Activity in Vivo

Oxidation of protein-bound methionine in Photofrin-photodynamic therapy-treated human tumor cells explored by methionine-containing peptide enrichment and quantitative proteomics approach

Antibody-Directed Phototherapy (ADP)

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