Author:
Thi Khanh Le, Clément Paris, Khadija Shahed Khan, Fran Robson, Wai-Lung Ng, Palma Rocchi
Publication Date:
01 May 2021
Source:
Trends in Biochemical Sciences
Description:
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently creating a global health emergency. This crisis is driving a worldwide effort to develop effective vaccines, prophylactics, and therapeutics. Nucleic acid (NA)-based treatments hold great potential to combat outbreaks of coronaviruses (CoVs) due to their rapid development, high target specificity, and the capacity to increase druggability. Here, we review key anti-CoV NA-based technologies, including antisense oligonucleotides (ASOs), siRNAs, RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas), and mRNA vaccines, and discuss improved delivery methods and combination therapies with other antiviral drugs.
Author:
Hajer Ziouziou, Clément Paris, Sébastien Benizri, Thi Khanh Le, Claudia Andrieu, Dang Tan Nguyen, Ananda Appavoo, David Taïeb, Frédéric Brunel, Ridha Oueslati, Olivier Siri, Michel Camplo, Philippe Barthélémy, Palma Rocchi
Publication Date:
27 Apr 2021
Description:
Heat shock protein 27 (Hsp27) has an established role in tumor progression and chemo-resistance of castration-resistant prostate cancer (CRPC). Hsp27 protects eukaryotic translation initiation factor 4E (eIF4E) from degradation, thereby maintaining survival during treatment. Phenazine derivative compound #14 was demonstrated to specifically disrupt Hsp27/eIF4E interaction and significantly delay castration-resistant tumor progression in prostate cancer xenografts. In the present work, various strategies of encapsulation of phenazine #14 with either DOTAU (N-[5′-(2′,3′-dioleoyl)uridine]-N′,N′,N′-trimethylammonium tosylate) and DOU-PEG2000 (5′-PEG2000-2′,3′-dioleoyluridine) nucleolipids (NLs) were developed in order to improve its solubilization, biological activity, and bioavailability. We observed that NLs-encapsulated phenazine #14-driven Hsp27-eIF4E interaction disruption increased cytotoxic effects on castration-resistant prostate cancer cell line and inhibited tumor growth in castration-resistant prostate cancer cell xenografted mice compared to phenazine #14 and NLs alone. Phenazine #14 NL encapsulation might represent an interesting nanostrategy for CRPC therapy.
Author:
Kenneth Omabe, Clément Paris, François Lannes, David Taïeb, Palma Rocchi
Publication Date:
21 Apr 2021
Description:
Prostate cancer (PC) is the most frequent male cancer in the Western world. Progression to Castration Resistant Prostate Cancer (CRPC) is a known consequence of androgen withdrawal therapy, making CRPC an end-stage disease. Combination of cytotoxic drugs and hormonal therapy/or genotherapy is a recognized modality for the treatment of advanced PC. However, this strategy is limited by poor bio-accessibility of the chemotherapy to tumor sites, resulting in an increased rate of collateral toxicity and incidence of multidrug resistance (MDR). Nanovectorization of these strategies has evolved to an effective approach to efficacious therapeutic outcomes. It offers the possibility to consolidate their antitumor activity through enhanced specific and less toxic active or passive targeting mechanisms, as well as enabling diagnostic imaging through theranostics. While studies on nanomedicine are common in other cancer types, only a few have focused on prostate cancer. This review provides an in-depth knowledge of the principles of nanotherapeutics and nanotheranostics, and how the application of this rapidly evolving technology can clinically impact CRPC treatment. With particular reference to respective nanovectors, we draw clinical and preclinical evidence, demonstrating the potentials and prospects of homing nanovectorization into CRPC treatment strategies.
Author:
Sébastien Benizri, Alexandra Gaubert, Charlotte Soulard, Étienne Gontier, Isabelle Svahn, Palma Rocchi, Gaëlle Vacher, Philippe Barthélémy
Publication Date:
01 Jan 2021
Source:
Biomaterials Science
Description:
Synthetic OligoNucleotides (ON) provide promising therapeutic tools for controlling specifically genetic expression in a broad range of diseases from cancers to viral infections. Beside their chemical stability and intracellular delivery, the controlled release of therapeutic sequences remains an important challenge for successful clinical applications. In this work, Lipid-OligoNucleotide (LON) conjugates stabilizing hydrogels are reported and characterized by rheology and cryo-scanning electron microscopy (cryo-SEM). These studies revealed that lipid conjugation of antisense oligonucleotides featuring partial self-complementarity resulted in entangled pearl-necklace networks, which were obtained through micelle-micelle interaction driven by duplex formation. Owing to these properties, the Lipid AntiSense Oligonucleotide (LASO) sequences exhibited a prolonged release after subcutaneous administration compared …
Author:
Guillaume Sicard, Clément Paris, Sarah Giacometti, Anne Rodallec, Joseph Ciccolini, Palma Rocchi, Raphaëlle Fanciullino
Publication Date:
29 Nov 2020
Description:
Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option—however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO …
Author:
Fran Robson, Khadija Shahed Khan, Thi Khanh Le, Clément Paris, Sinem Demirbag, Peter Barfuss, Palma Rocchi, Wai-Lung Ng
Publication Date:
03 Sep 2020
Description:
The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.
Author:
Yiwen Dong, Yu Chen, Dandan Zhu, Kangjie Shi, Chi Ma, Wenjie Zhang, Palma Rocchi, Lei Jiang, Xiaoxuan Liu
Publication Date:
10 Jun 2020
Source:
Journal of Controlled Release
Description:
RNA interference (RNAi) holds great promise for therapeutic applications. However, safe and successful clinical translation essentially requires further advancement of developing efficient delivery systems. Herein, we report that amphiphilic phospholipid peptide dendrimers (AmPPDs) could mediated effective delivery of siRNA targeting Hsp27 for treating castration-resistant prostate cancer (CRPC). AmPPDs bears natural lipid derivative DSPE as the hydrophobic tail and different dendritic l-lysine as the hydrophilic head, capable of compacting siRNA into nanoparticles to protect it from enzymatic degradation. Interestingly, DSPE-KK2, AmPPD bearing smaller hydrophilic dendron, promoting more efficient intracellular uptake and endosome release of the so-formed siRNA complexes, as well as better siRNA releasing ability, ultimately resulting in more potent gene silencing and anticancer effects both in vitro and in …
Author:
Asma Bourefis, Hajira Berredjem, Omar Djeffal, Palma Rocchi
Publication Date:
01 Jan 2020
Source:
Medical Technologies Journal
Description:
Prostate cancer (CaP) is the second most common cancer in men and a major public health problem. Clinical outcomes at diagnosis are heterogeneous and difficult to predict, so predictive and diagnostic markers are needed. Heat shock proteins (Hsps) such as Hsp27 are highly regulated in several malignant tumors. Basal Hsp27 levels in most human tissues are low compared to high levels in tumors.Objective: In this work, we evaluated, in subjects with CaP, the levels of expression of the Hsp27 antigen in tumor tissues and its association with tumor aggressiveness.Material and methods: The Immuno-Histo-Chimical (IHC) method was used to determine the expression of Hsp27 in 58 prostate cancer tissues and 4 prostate hyperplasia (BPH).Results: Tissue levels of Hsp27 were significantly higher in patients with CaP than in BPH (QSM= 153.43±0; P< 0.0001). In the case of aggressive cancer (Gleason score> 7), we found a very significant increase in Hsp27 protein (QSM= 169.73±84.26; P< 0.0001) compared to non-aggressive cancer (Gleason score≤ 7)(QSM= 123.92±91.36; P< 0.001).Conclusion: Overexpression of hsp27 in the tissues of patients with CaP compared to patients with BPH may be of diagnostic and/or prognostic interest and may be a therapeutic target in patients with prostate cancer.
Author:
Maria Katsogiannou, Jean-Baptiste Boyer, Alberto Valdeolivas, Elisabeth Remy, Laurence Calzone, Stéphane Audebert, Palma Rocchi, Luc Camoin, Anaïs Baudot
Publication Date:
01 Nov 2019
Description:
Background Prostate cancer is a major public health issue, mainly because patients relapse after androgen deprivation therapy. Proteomic strategies, aiming to reflect the functional activity of cells, are nowadays among the leading approaches to tackle the challenges not only of better diagnosis, but also of unraveling mechanistic details related to disease etiology and progression. Methods We conducted here a large SILAC-based Mass Spectrometry experiment to map the proteomes and phosphoproteomes of four widely used prostate cell lines, namely PNT1A, LNCaP, DU145 and PC3, representative of different cancerous and hormonal status. Results We identified more than 3000 proteins and phosphosites, from which we quantified more than 1000 proteins and 500 phosphosites after stringent filtering. Extensive exploration of this proteomics and phosphoproteomics dataset allowed characterizing housekeeping as well as cell-line specific proteins, phosphosites and functional features of each cell line. In addition, by comparing the sensitive and resistant cell lines, we identified protein and phosphosites differentially expressed in the resistance context. Further data integration in a molecular network highlighted the differentially expressed pathways, in particular migration and invasion, RNA splicing, DNA damage repair response and transcription regulation. Conclusions Overall, this study proposes a valuable resource toward the characterization of proteome and phosphoproteome of four widely used prostate cell lines and reveals candidates to be involved in prostate cancer progression for further experimental validation.
Author:
F Lannes, K Le Thi, C Cherif, S Benizri, L Fazli, C Paris, M Gleave, P Barthelemy, P Rocchi
Publication Date:
01 Nov 2019
Source:
Progrès en Urologie
Description:
ObjectifsL’évolution vers la résistance à la castration (RC) est inéluctable et intervient après 18 à 24 mois en moyenne chez des patients ayant un cancer de prostate (CP) avancé traités par hormonothérapie (HT). À ce stade l’arsenal thérapeutique se réduit drastiquement et de nouveaux traitements sont nécessaires. La protéine DDX5 est surexprimée dans les CPRC et fonctionne comme un co-activateur du récepteur aux androgènes (RA).MéthodesNous avons utilisé une banque de tissu de 752 biopsies de prostate pour étudier l’expression de DDX5 dans les CP, en fonction du Gleason et du stade de la maladie en utilisant un test t de Student. Nous avons également étudié l’impact de l’expression de DDX5 sur la survie sans récidive biologique par la méthode de Kaplan–Meier. Nous avons ensuite fait le design et le screening de plusieurs oligonucléotides antisens (ASO) contre l’ARNm de DDX5 permettant …
