Author:
Delphine Luvino, Salim Khiati, Khalid Oumzil, Palma Rocchi, Michel Camplo, Philippe Barthélémy
Publication Date:
28 Dec 2013
Source:
Journal of Controlled Release
Description:
A novel nucleoside lipid derived from dioleyl ketal was synthesized from uridine in three steps starting from dioleyl ketone. Electronic microscopy studies show that Ketals Nucleoside Lipids (KNL) self-assemble to form liposome-like structures in aqueous solutions. KNL is able to bind siRNA as demonstrated by electrophoresis experiment and standard ethidium bromide fluorescence displacement assay. Transfection assays of stable hepatic cell lines HupIRF, carrying a luciferase reporter gene demonstrate that KNL is able to transfect siRNA and exhibits protein knockdown more efficiently than its diester analog (DOTAU) and lipofectamine. Herein, we also report that KNLs are suitable transfecting reagents for the development of novel therapeutic approaches involving either siRNA or antisense oligonucleotide against human prostate cancer PC-3 cells resistant to chemotherapy.
Author:
Paola Posocco, Xiaoxuan Liu, Erik Laurini, Domenico Marson, Chao Chen, Cheng Liu, Maurizio Fermeglia, Palma Rocchi, Sabrina Pricl, Ling Peng
Publication Date:
05 Aug 2013
Source:
Molecular Pharmaceutics
Description:
Small interfering RNA (siRNA) have attracted considerable attention, as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing siRNA delivery vectors thanks to their unique, well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. We have recently disclosed the structurally flexible fifth-generation TEA-core PAMAM dendrimer (G5) as an effective nanocarrier for delivery of sticky siRNA bearing long complementary sequence overhangs (dA)n/(dT)n (n = 5 or 7). Here, using combined experimental/computational approaches, we successfully clarified (i) the underlying mechanisms of interaction between the dendrimer nanovector G5 and siRNA molecules bearing either complementary or noncomplementary sequence overhangs of different length and chemistry and (ii) the impact of siRNA …
Author:
Houda Saadi, Marion Seillier, Maria José Sandi, Sylvain Peuget, Christine Kellenberger, Gwenaëlle Gravis, Nelson J Dusetti, Juan L Iovanna, Palma Rocchi, Mohamed Amri, Alice Carrier
Publication Date:
01 Jan 2013
Source:
Results in Immunology
Description:
Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) plays an important role during cell stress response in synergy with the potent “genome-keeper” p53. In human, the gene encoding TP53INP1 is expressed at very high level in some pathological situations, such as inflammation and prostate cancer (PC). TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse, making TP53INP1 a relevant specific target for molecular therapy of Castration Resistant (CR) PC. In that context, detection of TP53INP1 in patient biological fluids is a promising diagnostic avenue. We report here successful development of a new Enzyme-Linked Immunosorbent Assay (ELISA) detecting TP53INP1, taking advantage of molecular tools (monoclonal antibodies (mAbs) and recombinant proteins) generated in the laboratory during the course of basic functional investigations …
Author:
Virginie Baylot, Maria Katsogiannou, Claudia Andrieu, David Taieb, Julie Acunzo, Sophie Giusiano, Ladan Fazli, Martin Gleave, Carmen Garrido, Palma Rocchi
Publication Date:
01 Dec 2012
Source:
Molecular Therapy
Description:
Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function …
Author:
Julie Acunzo, Maria Katsogiannou, Palma Rocchi
Publication Date:
01 Oct 2012
Source:
The international journal of biochemistry & cell biology
Description:
Hsp27, αB-crystallin and HSP22 are ubiquitous small heat shock proteins (sHsp) whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. These sHsp protect cells from otherwise lethal conditions mainly by their involvement in cell death pathways such as necrosis, apoptosis or autophagy. At a molecular level, the mechanisms accounting for sHsp functions in cell death are (1) prevention of denatured proteins aggregation, (2) regulation of caspase activity, (3) regulation of the intracellular redox state, (4) function in actin polymerization and cytoskeleton integrity and (5) proteasome-mediated degradation of selected proteins. In cancer cells, these sHsp are often overexpressed and associated with increased tumorigenicity, cancer cells metastatic potential and resistance to chemotherapy. Altogether, these properties suggest that Hsp27, αB-crystallin and …
Author:
J Acunzo, V Baylot, M Katsogiannou, C Andrieu, P Rocchi
Publication Date:
01 Sep 2012
Source:
Annales d'Endocrinologie
Description:
Objectif.–Les phéochromocytomes/paragangliomes métastatiques (PPM) sont des tumeurs rares à l’histoire naturelle hétérogène. Nous avons étudié l’efficacité anti-tumorale du temozolomide chez les patients présentant un PPM. Matériel et méthodes.–Quinze patients consécutifs avec un PPM progressif (n= 14) ou symptomatique (n= 1) ont reçu du temozolomide. La dose intensité moyenne était de 171 mg/m2/jour (IC95% 160.7–181) pendant cinq jours, tous les 28jours. Le critère de jugement principal était la survie sans progression (SSP).Résultats.–Parmi les 15 patients inclus, il y avait 12 hommes (80%), âge médian de 43 ans et dix patients étaient porteurs d’une mutation du gène SDHB. Les cinq réponses partielles (33%) furent observées chez cinq patients SDHB: taux de réponse de 50% dans cette population. Avec un suivi médian de 29mois, la survie globale médiane n’était pas atteinte et la SSP …
Author:
Sophie Giusiano, Virginie Baylot, Claudia Andrieu, Ladan Fazli, Martin Gleave, Juan Lucio Iovanna, Colette Taranger‐Charpin, Stéphane Garcia, Palma Rocchi
Publication Date:
01 Sep 2012
Description:
BACKGROUND Prostate cancer (PC) is one of the most common malignancies in industrialized countries, and the second leading cause of cancer‐related death in the United States. We recently showed that over‐expression of tumor protein 53‐induced nuclear protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. Moreover, treatment of castration‐sensitive (CS) LNCaP tumor cells with a TP53INP1 antisense oligonucleotide (TP53INP1 ASO) inhibits proliferation and induces apoptosis. The aim of this study was to investigate variations of TP53INP1 expression in PC during androgen withdrawal therapy and in castration‐resistant prostate cancer (CRPC). METHODS Quantitative measurements of immunohistochemical expression of TP53INP1 using high‐throughput densitometry, assessed on digitized microscopic tissue micro …
Author:
Tianzhu Yu, Xiaoxuan Liu, Anne‐Laure Bolcato‐Bellemin, Yang Wang, Cheng Liu, Patrick Erbacher, Fanqi Qu, Palma Rocchi, Jean‐Paul Behr, Ling Peng
Publication Date:
20 Aug 2012
Source:
Angewandte Chemie International Edition
Description:
The potent ability of small interfering RNA (siRNA) to specifically and efficiently inhibit the expression of complementary RNA transcripts offers a promising alternative therapeutic approach for various diseases.[1] However, the major challenge facing siRNA-based therapy is the requirement of a safe and efficient delivery system for the siRNA.[2] Although viral vectors are highly efficient, their potential inflammatory, immunogenic, and mutagenic effects make them a safety risk and underline the urgent need for nonviral alternatives. Cationic lipids and polymers are the most common nonviral vectors: both are able to assemble the siRNA, through electrostatic interaction, into stable complexes, which can protect the siRNA from degradation and promote cell uptake.[3–5] But inadequate release of siRNA into the cytosol often constitutes one of the main obstacles for efficient nonviral delivery. Lipid vectors are presumed to …
Author:
Yi Xia, Menghua Wang, Olivier Demaria, Jingjie Tang, Palma Rocchi, Fanqi Qu, Juan L Iovanna, Lena Alexopoulou, Ling Peng
Publication Date:
14 Jun 2012
Source:
Journal of medicinal chemistry
Description:
A novel bitriazolyl acyclonucleoside was discovered to exhibit powerful antiproliferative effects on different cancer cell lines through caspase-dependent apoptosis and at the same time stimulate the immune response in dendritic cells via Toll-like receptor 7 (TLR7) signaling. This promising compound with dual anticancer and immunomodulatory activity may represent a new generation of highly efficacious drug candidates for use in cancer therapy.
Author:
Yi Xia, Yang Liu, Palma Rocchi, Menghua Wang, Yuting Fan, Fanqi Qu, Juan L Iovanna, Ling Peng
Publication Date:
28 May 2012
Description:
Issued from a lead optimization process, we have identified a novel triazole nucleoside analog which elicits potent anticancer activity on drug-resistant pancreatic cancer. Most importantly, this compound targets heat shock response pathways by down-regulation of heat shock transcription factor 1 and consequential down-regulation of multiple heat shock proteins HSP27, HSP70 and HSP90. Down-regulation of these proteins caused the shut-down of several oncogenic pathways and caspase-dependent apoptosis resulting in a potent anticancer effect in vitro and in vivo. These results demonstrate the potential rewards gained in searching for anticancer candidates with multimodal actions on heat shock response pathways via HSF1 down-regulation.
