title: Analysis of the in vitro and in vivo effects of photodynamic therapy on prostate cancer by using new photosensitizers, protoporphyrin IX-polyamine derivatives.
abstract: Photodynamic therapy, using porphyrins as photosensitizers (PS), has been approved in treatment of several solid tumors. However, commonly used PS induce death but also resistance pathways in cancer cells and an alteration of surrounding normal tissues. Because polyamines (PA) are actively accumulated in cancer cells by the Polyamine Transport System (PTS), they may enable PS to specifically target cancer cells. Here, we investigated whether new protoporphyrin IX-polyamine derivatives were effective PS against prostate cancer and whether PA increased PDT specificity after 630nm irradiation.
  
  
  
  CHO and CHO-MG cells (differing in their PTS activity) were used to assess efficacy of polyamine vectorization. MTT assays were performed on human prostate non-malignant (RWPE-1) and malignant (PC-3, DU 145 and LNCaP) cell lines to test PS phototoxicity. ROS generation, DNA fragmentation and cell signalling were assessed by ELISA/EIA, western-blots and gel shift assays. Finally, PS effects were studied on tumor growth in nude mice.
  
  
  
  Our PS were more effective on cancer cells compared to non-malignant cells and more effective than PpIX alone. PpIX-PA generated ROS production involved in induction of apoptotic intrinsic pathways. Different pathways involved in apoptosis resistance were studied: PS inhibited Bcl-2, Akt, and NF-κB but activated p38/COX-2/PGE2pathways which were not implicated in apoptosis resistance in our model. In vivo experiments showed PpIX-PA efficacy was greater than results obtained with PpIX.
  
  
  
  All together, our results showed that PpIX-PA exerted its maximum effects without activating resistance pathways and appears to be a good candidate for prostate cancer PDT treatment.
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France.
authors.forename: Chloë
authors.initials: C
authors.lastname: Fidanzi-Dugas
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France. Electronic address: bertrand.liagre@unilim.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Liagre
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chemin
authors.affiliation: Université de Limoges, Homéostasie Cellulaire et Pathologie, EA 3842, 2 rue du Docteur Marcland, F-87025 Limoges, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Perraud
authors.affiliation: Université de Limoges, CIM, UMR CNRS 7276, 2 rue du Dr Marcland, F-87000 Limoges, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Carrion
authors.affiliation: Laboratoire de recherche et d'analyses de la Haute-Vienne, Avenue du Professeur Joseph de Léobardy, 87005 Limoges, France.
authors.forename: Claude-Yves
authors.initials: CY
authors.lastname: Couquet
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Granet
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sol
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, F-87060 Limoges, France.
authors.forename: David Yannick
authors.initials: DY
authors.lastname: Léger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D006801:Humans; D008297:Male; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011073:Polyamines / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011524:Protoporphyrins / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017319:Photosensitizing Agents; D011073:Polyamines; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C028025:protoporphyrin IX
keywords: Apoptosis; Cyclooxygenase; Photodynamic therapy; Porphyrin; Prostate cancer