Purpose: Clinical and epidemiologic data suggest that obesity is associated with more aggressive forms of prostate cancer, poor prognosis, and increased mortality. C-terminal-binding protein 1 (CtBP1) is a transcription repressor of tumor suppressor genes and is activated by NADH binding. High calorie intake decreases intracellular NAD þ /NADH ratio. The aim of this work was to assess the effect of high-fat diet (HFD) and CtBP1 expression modulation over prostate xenograft growth. Experimental Design: We developed a metabolic syndrome-like disease in vivo model by feeding male nude mice with HFD during 16 weeks. Control diet (CD)-fed animals were maintained at the same conditions. Mice were inoculated with PC3 cells stable transfected with shCtBP1 or control plasmids. Genome-wide expression profiles and Gene Set Enrichment Analysis (GSEA) were performed from PC3. shCtBP1 versus PC3.pGIPZ HFD-fed mice tumors.Results: No significant differences were observed in tumor growth on CD-fed mice; however, we found that only 60% of HFD-fed mice inoculated with CtBP1-depleted cells developed a tumor. Moreover these tumors were significantly smaller than those generated by PC3.pGIPZ control xenografts. We found 823 genes differentially expressed in shCtBP1 tumors from HFD-fed mice. GSEA from expression dataset showed that most of these genes correspond to cell adhesion, metabolic process, and cell cycle.Conclusions: Metabolic syndrome-like diseases and CtBP1 expression cooperate to induce prostate tumor growth. Hence, targeting of CtBP1 expression might be considered for prostate cancer management and therapy in the subset of patients with metabolic syndromes. Clin Cancer Res; 20(15); 4086-95. Ó2014 AACR.

Biofilm-associated diseases account for 80% of all infections in humans. Due to the emergence of antibiotic resistances, alternative therapies such as Photodynamic Inactivation (PDI) of microorganisms have emerged. Porphyrins with intrinsic positive charges have been proposed as successful photosensitizers (PSs) against microorganisms. We have recently designed the new synthetic porphyrin 5,10,15,20-tetrakis[4-(3-N,Ndimethylammoniumpropoxy)phenyl]porphyrin (TAPP) containing four basic amine groups in the periphery of the tetrapyrrolic macrocycle, which can acquire positive charges at physiological pH, thus favouring the interaction with biomembranes. Illumination of planktonic cultures of Staphylococcus aureus at 180 J/cm 2 in the presence of 2.5 µM TAPP induced complete bacteria eradication. For the TAPP-PDI treatment of S. aureus biofilms, higher light fluences and PS concentrations were needed. Employing 20 µM TAPP and 180 J/cm 2 , around 3-log CFU reduction were obtained. In order to determine the efficacy of TAPP-PDI on Gram-negative bacteria, we performed planktonic and biofilm assays employing Pseudomonas aeruginosa. Much higher TAPP doses as compared to S. aureus were needed to achieve planktonic bacteria photosensitization (3-log CFU reduction at 20 µM TAPP and 180 J/cm 2). On the other hand, high concentrations of TAPP were non toxic to P. aeruginosa growing on biofilms, and employing 30 µM TAPP and 180 J/cm 2 we obtained 3-log CFU reduction. The main conclusion of the present work is that TAPP is a promising and efficient PS capable of promoting photodynamic killing of both Gram-negative and-positive in planktonic bacteria, though more effectively in the latter. In addition, TAPP-PDI induces similar photoinactivation rates in both bacteria types growing on biofilms, with lower dark toxicity in the Gram-negative one. Highlights A porphyrin which is charged at physiological pH was used for S. aureus inactivation. Photodynamic treatment induced complete eradication of S. aureus in planktonic state. The same treatment induced 3 logs of CFU reduction of S. aureus biofilms. Gram-positive and-negative bacteria biofilms were equally photosensitized.

The use of endogenous protoporphyrin IX after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). We have previously reported that the conjugation of ALA dendrimers enhances porphyrin synthesis. The first aim of this work was to evaluate the ability of ALA dendrimers carrying 6 and 9 ALA residues (6m-ALA and 9m-ALA) to photosensitise cancer cells. For this aim, we employed LM3 mammary carcinoma cells. In these tumour cells, at low concentrations porphyrin synthesis from dendrimers was higher compared to ALA, whereas at high concentrations, porphyrin synthesis was similar from both compounds. Topical application of ALA dendrimers on the skin overlying a subcutaneous LM3 implanted tumour showed no diffusion of the molecules either to distant skin sites or to the adjacent tumour, suggesting a promising use of the ALA macromolecules in superficial cancer models. As a second objective, we proposed the use of ALA-dendrimers in vascular PDT for the treatment of atherosclerosis. Thus, we focused our studies on ALA-dendrimer's selectivity towards macrophages in comparison with endothelial cells. For this aim we employed Raw 264.7 macrophages and HMEC-1 microvasculature cells. Porphyrin synthesis induced in macrophages by 6m-ALA and 9m-ALA (3 h, 0.025 mM) was 6 and 4.6 times higher respectively compared to the endothelial cell line, demonstrating the high affinity of ALA dendrimers for macrophages. On the other hand, ALA employed at low concentrations was slightly selective (1.7-fold) for macrophages. Inhibition studies suggested that ALA dendrimer uptake in macrophages is mainly mediated by caveloae-mediated endocytosis. Our main conclusion is that in addition to being promising molecules in PDT of superficial cancer, ALA dendrimers may also find applications in vascular PDT, since in vitro they showed selectivity to the macrophage component of the atheromatous plaque, as compared to the vascular endothelium.