Author:
Maria Katsogiannou, Claudia Andrieu, Virginie Baylot, Anaïs Baudot, Nelson J Dusetti, Odile Gayet, Pascal Finetti, Carmen Garrido, Daniel Birnbaum, François Bertucci, Christine Brun, Palma Rocchi
Publication Date:
01 Dec 2014
Source:
Molecular & Cellular Proteomics
Description:
Previously, we identified the stress-induced chaperone, Hsp27, as highly overexpressed in castration-resistant prostate cancer and developed an Hsp27 inhibitor (OGX-427) currently tested in phase I/II clinical trials as a chemosensitizing agent in different cancers. To better understand the Hsp27 poorly-defined cytoprotective functions in cancers and increase the OGX-427 pharmacological safety, we established the Hsp27-protein interaction network using a yeast two-hybrid approach and identified 226 interaction partners. As an example, we showed that targeting Hsp27 interaction with TCTP, a partner protein identified in our screen increases therapy sensitivity, opening a new promising field of research for therapeutic approaches that could decrease or abolish toxicity for normal cells. Results of an in-depth bioinformatics network analysis allying the Hsp27 interaction map into the human interactome underlined …
Author:
Xiaoxuan Liu, Cheng Liu, Chao Chen, Melanie Bentobji, Francine Azario Cheillan, Jeanne Thomassin Piana, Fanqi Qu, Palma Rocchi, Ling Peng
Publication Date:
01 Nov 2014
Source:
Nanomedicine: Nanotechnology, Biology and Medicine
Description:
Small interfering RNAs (siRNA) are emerging as novel therapeutic agents, providing competent delivery systems that are available. Dendrimers, a special family of synthetic macromolecules, represent an exciting delivery platform by virtue of their well-defined dendritic structure and unique multivalency and cooperativity confined within a nanoscale volume. Here, we report a Dicer-substrate siRNA (dsiRNA) which, when delivered using a structurally flexible triethanolamine-core poly(amidoamine) dendrimer of generation 5 as the nanocarrier, gives rise to a much greater RNAi response than that produced with conventional siRNA. Further decoration of the dsiRNA/dendrimer complexes with a dual targeting peptide simultaneously promoted cancer cell targeting through interacting with integrins and cell penetration via the interaction with neuropilin-1 receptors, which led to improved gene silencing and anticancer …
Author:
Xiaoxuan Liu, Jiehua Zhou, Tianzhu Yu, Chao Chen, Qiang Cheng, Kheya Sengupta, Yuanyu Huang, Haitang Li, Cheng Liu, Yang Wang, Paola Posocco, Menghua Wang, Qi Cui, Suzanne Giorgio, Maurizio Fermeglia, Fanqi Qu, Sabrina Pricl, Yanhong Shi, Zicai Liang, Palma Rocchi, John J Rossi, Ling Peng
Publication Date:
27 Oct 2014
Source:
Angewandte Chemie International Edition
Description:
siRNA delivery remains a major challenge in RNAi‐based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self‐assemble into adaptive supramolecular assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addition, this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer‐based adaptive supramolecular assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer‐based self‐assembled drug delivery in biomedical applications.
Author:
Maria Katsogiannou, Claudia Andrieu, Palma Rocchi
Publication Date:
06 Oct 2014
Source:
Frontiers in genetics
Description:
Understanding the mechanisms that control stress-induced survival is critical to explain how tumors frequently resist to treatment and to improve current anti-cancer therapies. Cancer cells are able to cope with stress and escape drug toxicity by regulating heat shock proteins (Hsps) expression and function. Hsp27 (HSPB1), a member of the small Hsp family, represents one of the key players of many signaling pathways contributing to tumorigenicity, treatment resistance, and apoptosis inhibition. Hsp27 is overexpressed in many types of cancer and its functions are regulated by post-translational modifications, such as phosphorylation. Protein phosphorylation is the most widespread signaling mechanism in eukaryotic cells, and it is involved in all fundamental cellular processes. Aberrant phosphorylation of Hsp27 has been associated with cancer but the molecular mechanisms by which it is implicated in cancer development and progression remain undefined. This mini-review focuses on the role of phosphorylation in Hsp27 functions in cancer cells and its potential usefulness as therapeutic target in cancer.
Author:
Xiaoxuan Liu, Cheng Liu, Carlo V Catapano, Ling Peng, Jiehua Zhou, Palma Rocchi
Publication Date:
01 Jul 2014
Source:
Biotechnology advances
Description:
RNAi-based nucleic acid molecules have attracted considerable attention as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing nanocarriers for nucleic acid delivery thanks to their unique well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. The present review offers a brief overview of the structurally flexible triethanolamine-core poly(amidoamine) (PAMAM) dendrimers developed in our group as nanovectors for the delivery of RNAi therapeutics. Their excellent activity for delivering different RNAi therapeutics in various disease models in vitro and in vivo will be highlighted here.
Author:
Julie Acunzo, Virginie Baylot, Alan So, Palma Rocchi
Publication Date:
01 Jul 2014
Source:
Cancer treatment reviews
Description:
The translationally controlled tumor protein (TCTP) is a highly conserved protein present in eukaryotic organisms. This protein, located both in the cytoplasmic and the nucleus, is expressed in various tissues and is regulated in response to a wide range of extracellular stimuli. TCTP interacts with itself and other protein including MCL1 and p53. TCTP has been shown to play an important role in physiological events, such as cell proliferation, cell death and immune responses but also in stress response and tumor reversion. Moreover, TCTP expression is associated with malignancy and chemoresistance. In this review, we will evaluate pathways regulated by TCTP and current inhibitory strategy to target TCTP in cancerous diseases.
Author:
Christine Pasero, Gwenaelle Gravis, Mathilde Guerin, Palma Rocchi, Jeanne Thomassin, Samuel Granjeaud, Jochen Walz, Naji Salem, Slimane Dermeche, Serge Brunelle, Daniel Olive
Publication Date:
20 May 2014
Source:
Journal of Clinical Oncology
Description:
e16025 Background: Immunotherapy is now investigated as a promising alternative treatment for metastatic prostate cancer (PC) patients. Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC patients (pts) were divided according the time of castration response, with an 18-months cutoff value: 14 pts with long castration response (LCR, median = 73.5 months), and 12 pts with short castration response (SCR, median = 10.58 months), with a median overall survival of 112 months and 28.8 months respectively. Circulating …
Author:
Julie Acunzo, Claudia Andrieu, Virginie Baylot, Alan So, Palma Rocchi
Publication Date:
01 Apr 2014
Source:
Current drug targets
Description:
Heat shock protein 27 (Hsp27), induced by heat shock, environmental and pathophysiological stressors, is a multidimensional protein that acts as a protein chaperone and an antioxidant. This protein plays a major role in the inhibition of apoptosis and actin cytoskeletal remodeling. This stress-activated protein is up-regulated in many cancers and is associated with poor prognosis as well as treatment resistance by protecting cells from therapeutic agent that normally induces apoptosis. This review highlights the most recent findings and role of Hsp27 in cancer and the different strategies to target and inhibit Hsp27 for clinical purposes.
Author:
Cheng Liu, Xiaoxuan Liu, Palma Rocchi, Fanqi Qu, Juan L Iovanna, Ling Peng
Publication Date:
19 Mar 2014
Source:
Bioconjugate chemistry
Description:
Successful therapeutic implementation of RNA interference critically depends on systems able to safely and efficiently deliver small interfering RNA (siRNA). Dendrimers are emerging as appealing nanovectors for siRNA delivery by virtue of their unique well-defined dendritic nanostructure within which is confined an intriguing cooperativity and multivalency. We have previously demonstrated that structurally flexible triethanolamine (TEA) core poly(amidoamine) (PAMAM) dendrimers of high generations are effective nanovectors for siRNA delivery in vitro and in vivo. In the present study, we have developed arginine-terminated dendrimers with the aim of combining and harnessing the unique siRNA delivery properties of the TEA-core PAMAM dendrimer and the cell-penetrating advantages of the arginine-rich motif. A generation 4 dendrimer of this family (G4Arg) formed stable dendriplexes with siRNA, leading to …
Author:
Aurélie de Thonel, Adonis Hazoume, V Kochin, K Isoniemi, Gaetan Jego, E Fourmaux, Arlette Hammann, H Mjahed, O Filhol, Olivier Micheau, P Rocchi, Valérie Mezger, John E Eriksson, Vivek M Rangnekar, Carmen Garrido
Publication Date:
01 Jan 2014
Source:
Cell death & disease
Description:
The proapoptotic protein, prostate apoptosis response-4 (Par-4), acts as a tumor suppressor in prostate cancer cells. The serine/threonine kinase casein kinase 2 (CK2) has a well-reported role in prostate cancer resistance to apoptotic agents or anticancer drugs. However, the mechanistic understanding on how CK2 supports survival is far from complete. In this work, we demonstrate both in rat and humans that (i) Par-4 is a new substrate of the survival kinase CK2 and (ii) phosphorylation by CK2 impairs Par-4 proapoptotic functions. We also unravel different levels of CK2-dependent regulation of Par-4 between species. In rats, the phosphorylation by CK2 at the major site, S124, prevents caspase-mediated Par-4 cleavage (D123) and consequently impairs the proapoptotic function of Par-4. In humans, CK2 strongly impairs the apoptotic properties of Par-4, independently of the caspase-mediated cleavage of Par-4 …
