Document Detail


Chain-dependent photocytotoxicity of tricationic porphyrin conjugates and related mechanisms of cell death in proliferating human skin keratinocytes.
MedLine Citation:
PMID:  20691164     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Photodynamic therapy (PDT) is a poor treatment option for nodular basal cell carcinomas and squamous cell carcinomas. As a result, the search for new photosensitizers with better effectiveness is of current interest. The photocytotoxicity of conjugates (P-R) of a water-soluble tri-cationic porphyrin (P-H) having similar efficiency of production of singlet oxygen, the PDT cytotoxin, has been assessed in vitro. Links between uptake, intracellular localization, photooxidative stress, photocytotoxicity and ability to induce programmed cell death are established. Conjugates bearing methyl (P-Me), Di-O-isopropylidene-(-d-galactopyranosyl (P-OGal) or N,N'-dicyclohexylureidooxycarbonyl (P-DDC) chains are efficiently taken-up by proliferating NCTC 2544 keratinocytes. The relative order of photocytotoxicity is P-OGal >P-DDC=P-Me≫P-H. The photocytotoxic potential of P-Me, P-OGal and P-DDC equals that of endogenous protoporphyrin IX induced by δ-aminolevulinic acid or its esters, the pro-drugs currently employed for PDT of skin lesions. Microfluorometry shows that P-Me, P-OGal, and P-DDC localize in endocytotic or pinocytotic vesicles but not in mitochondria or nucleus. Absence of annexin V binding, caspase activation or chromatin condensation suggests that cell photosensitization by P-R does not induce apoptosis. On the other hand, P-OGal photocytotoxicity correlates with appearance of multiple vesicles that have hallmarks of autophagy compartments, being decorated with the marker LC3 in cells transfected with an expression vector encoding GFP-LC3. p38 and JNK phosphorylation and inhibition of ERK1/2 phosphorylation suggest close relationship between mortality of NCTC 2544 keratinocytes and MAPK pathway impairment. Given their potentially easy formulation, water-soluble P-R are promising powerful photosensitizers for PDT of skin lesions.
Authors:
João Nuno Silva; Antoine Galmiche; João P C Tomé; Agnès Boullier; Maria G P M S Neves; Eduarda M P Silva; Jean-Claude Capiod; José A S Cavaleiro; René Santus; Jean-Claude Mazière; Paulo Filipe; Patrice Morlière
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-04
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-20     Completed Date:  2010-10-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1373-85     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Hospital de Santa Maria, Clinica Universitária de Dermatologia, Lisboa, Portugal.
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MeSH Terms
Descriptor/Qualifier:
Annexin A5 / analysis
Apoptosis / drug effects*
Autophagy / drug effects
Caspases / metabolism
Cells, Cultured
Humans
Keratinocytes / drug effects*
Microscopy, Fluorescence
Mitogen-Activated Protein Kinases / physiology
Oxidative Stress
Photochemotherapy*
Porphyrins / pharmacology*
Chemical
Reg. No./Substance:
0/Annexin A5; 0/Porphyrins; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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